Novel arginase inhibitors

ABSTRACT

The present invention relates to novel arginase inhibitors of formula (I). These novel compounds are useful in the treatment of diseases that are associated with arginase activity, such as asthma, allergic rhinitis and COPD (chronic obstructive pulmonary disease).

The present invention relates to novel arginase inhibitors. These novelcompounds are useful in the treatment of diseases that are associatedwith arginase activity, such as asthma, allergic rhinitis and COPD(chronic obstructive pulmonary disease).

Arginase is a manganese-containing enzyme. The reaction catalyzed bythis enzyme is: arginine+H₂→ornithine+urea. Arginase catalyzes the fifthand final step in the urea cycle, a series of biochemical reactions inmammals during which the body disposes of harmful ammonia.

In most mammals, two isozymes of this enzyme exist; the first, ArginaseI, functions in the urea cycle, and is located primarily in thecytoplasm of hepatocytes (liver cells). The second isozyme, Arginase II,has been implicated in the regulation of intracellulararginine/ornithine levels. It is located in mitochondria of severaltissues in the body, with most abundance in the kidney and prostate. Itmay be found at lower levels in macrophages, lactating mammary glands,and brain. The second isozyme may be found in the absence of other ureacycle enzymes.

Allergic asthma is a chronic inflammatory airways' disease,characterized by allergen-induced early and late bronchial obstructivereactions, airway hyperresponsiveness (AHR), airway inflammation andairway remodelling. Recent ex vivo and in vivo studies in animal modelsand asthmatic patients have indicated that arginase plays a central rolein all these features. Thus, increased arginase activity in the airwaysinduces reduced bioavailability of L-arginine to constitutive (cNOS) andinducible (iNOS) nitric oxide synthases, causing a deficiency ofbronchodilating and anti-inflammatory NO, as well as increased formationof peroxynitrite, which may be involved in allergen-induced airwaysobstruction, AHR and inflammation. In addition, both via reduced NOproduction and enhanced synthesis of L-ornithine, increased arginaseactivity may be involved in airway remodelling by promoting cellproliferation and collagen deposition in the airway wall. Therefore,arginase inhibitors have therapeutic potential in the treatment of acuteand chronic asthma. Boron-containing arginase inhibitors are describedin WO 2016/108707 A1. However, so far, no arginase inhibitors areavailable for therapeutic treatment of asthma.

It has therefore been the object to provide novel arginase inhibitorswhich may be used for the treatment of diseases that are associated witharginase activity, such as asthma and COPD.

The present invention provides compounds of formula (I):

whereinn is 1 or 2;R¹ is hydrogen or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted;R² is hydrogen or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted, and R³ is hydrogen; orR² and R³ together are part of an optionally substitutedheterocycloalkyl or heteroaryl group; andR⁴ is hydrogen or methyl.or a pharmaceutically acceptable salt, solvate or hydrate or apharmaceutically acceptable formulation thereof.

According to a preferred embodiment, R⁴ is hydrogen.

According to a further preferred embodiment, R¹ is an alkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group,all of which groups may optionally be substituted.

Further preferably, if R³ is hydrogen, also R² is hydrogen.

Moreover preferably, R² and R³ together are part of an optionallysubstituted heterocycloalkyl group comprising 5 or 6 ring atoms selectedfrom C, N, O and S or part of an optionally substituted heteroaryl groupcomprising 5 or 6 ring atoms selected from C, N, O and S.

Further preferably, n is 1.

Moreover preferably, n is 2.

Further preferably, R¹ is a group of formula —CH₂—C(═O)—NH—R⁵, whereinR⁵ is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted.

Moreover preferably, R¹ is a group of formula —CH₂—CH₂—C(═O)—NH—R⁵,wherein R⁵ is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted.

Further preferably, R¹ is a group of formula —CH₂—C(═O)—N(CH₃)—R⁵,wherein R⁵ is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted.

Moreover preferably, R¹ is a group of formula -L¹-Cy¹-L²-Cy², wherein L¹and L² are independently selected from a bond, a C₁₋₄ alkyl group or aC₁₋₄ heteroalkyl group; Cy¹ is a C₃₋₇ cycloalkylene group, aheterocycloalkylene group containing from 3 to 7 ring atoms selectedfrom O, S, N and C, a phenylene group or a heteroarylene groupcontaining 5 or 6 ring atoms selected from O, S, N and C, all of whichgroups may optionally be substituted; and Cy² is a C₃₋₇ cycloalkylgroup, a heterocycloalkyl group containing from 3 to 7 ring atomsselected from O, S, N and C, a phenyl group or a heteroaryl groupcontaining 5 or 6 ring atoms selected from O, S, N and C, all of whichgroups may optionally be substituted.

Especially preferred compounds of formula (I) are compounds of formula(II):

wherein R⁵ is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted;or a pharmaceutically acceptable salt, solvate or hydrate or apharmaceutically acceptable formulation thereof.

Moreover especially preferred compounds of formula (I) are compounds offormula (III):

wherein R⁵ is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted;or a pharmaceutically acceptable salt, solvate or hydrate or apharmaceutically acceptable formulation thereof.

Preferably, R⁵ is a group of formula —CH₂—R⁶, —CH₂CH₂—R⁶ or —CH(CH₃)—R⁶wherein R⁶ is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted.

Especially preferably, R⁵ is a group of formula —CH₂—R⁶ or —CH₂CH₂—R⁶;most preferably, R⁵ is a group of formula —CH₂—R⁶.

Preferably, R⁶ is a C₁₋₄ alkyl, a C₂₋₄ alkenyl, a C₂₋₄ alkynyl or a C₁₋₄heteroalkyl group.

Further preferably, R⁶ is selected from the following groups, all ofwhich may optionally be substituted: C₃₋₇ cycloalkyl, phenyl,heterocycloalkyl containing from 3 to 7 ring atoms selected from C, N, Oand S and heteroaryl containing 5 or 6 ring atoms selected from C, N, Oand S.

Moreover preferably, R⁶ is an optionally substituted phenyl group or anoptionally substituted heteroaryl group containing 5 or 6 ring atomsselected from C, N, O and S.

Especially preferably, R⁶ is a phenyl group or a pyridyl group, all ofwhich may optionally be substituted, especially by one or two F or Clatoms.

Further especially preferred compounds of formula (I), (II) or (III) arecompounds of formula (I), (II) or (III) given in the examples or apharmaceutically acceptable salt, solvate or hydrate or apharmaceutically acceptable formulation thereof.

The expression alkyl refers to a saturated, straight-chain or branchedhydrocarbon group that contains from 1 to 20 carbon atoms, preferablyfrom 1 to 12 carbon atoms, especially from 1 to 6 (e.g. 1, 2, 3 or 4)carbon atoms, for example a methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl,2,2-dimethylbutyl or n-octyl group. Furthermore, the term alkyl refersto groups in which one or more hydrogen atoms have been replaced by ahalogen atom (preferably F or Cl) such as, for example, a2,2,2-trichloroethyl or a trifluoromethyl group.

The expressions alkenyl and alkynyl refer to at least partiallyunsaturated, straight-chain or branched hydrocarbon groups that containfrom 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms,especially from 2 to 6 (e.g. 2, 3 or 4) carbon atoms, for example anethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethinyl,propinyl, butinyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.Preferably, alkenyl groups have one or two (especially preferably one)double bond(s), and alkynyl groups have one or two (especiallypreferably one) triple bond(s). Furthermore, the terms alkenyl andalkynyl refer to groups in which one or more hydrogen atoms have beenreplaced by a halogen atom (preferably F or Cl).

The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl groupin which one or more (preferably 1, 2 or 3) carbon atoms have beenreplaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon orsulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or agroup of formula SO or SO₂. Accordingly, the expression heteroalkyl alsorefers to a carboxylic acid or to a group derived from a carboxylicacid, such as, for example, acyl, acylalkyl, alkoxy-carbonyl, acyloxy,acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy. Furthermore, theterm heteroalkyl refers to groups in which one or more hydrogen atomshave been replaced by a halogen atom (preferably F or Cl).

Preferably, a heteroalkyl group contains from 1 to 12 carbon atoms andfrom 1 to 4 hetero atoms selected from oxygen, nitrogen and sulphur(especially oxygen and nitrogen). Especially preferably, a heteroalkylgroup contains from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms and 1, 2 or3 (especially 1 or 2) hetero atoms selected from oxygen, nitrogen andsulphur (especially oxygen and nitrogen). The term C₁₋₆ heteroalkylrefers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1,2 or 3 heteroatoms selected from O, S and/or N (especially O and/or N).The term C₁₋₄ heteroalkyl refers to a heteroalkyl group containing from1 to 4 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and/orN (especially O and/or N).

Examples of heteroalkyl groups are groups of formulae: R^(a)—O—Y^(a)—,R^(a)—S—Y^(a)—, R^(a)—SO—Y^(a)—, R^(a)—SO₂—Y^(a)—,R^(a)—N(R^(b))—SO₂—Y^(a)—, R^(a)—SO₂—N(R^(b))—Y^(a)—,R^(a)—N(R^(b))—Y^(a)—, R^(a)—CO—Y^(a)—, R^(a)—O—CO—Y^(a)—,R^(a)—CO—O—Y^(a)—, R^(a)—CO—N(R^(b))—Y^(a)—, R^(a)—N(R^(b))—CO—Y^(a)—,R^(a)—O—CO—N(R^(b))—Y^(a)—, R^(a)—N(R^(b))—CO—O—Y^(a)—,R^(a)—N(R^(b))—CO—N(R^(c))—Y^(a)—, R^(a)—O—CO—O—Y^(a)—,R^(a)—N(R^(b))—C(═NR^(d))—N(R^(c))—Y^(a)—, R^(a)—CS—Y^(a)—,R^(a)—O—CS—Y^(a)—, R^(a)—CS—O—Y^(a)—, R^(a)—CS—N(R^(b))—Y^(a)—,R^(a)—N(R^(b))—CS—Y^(a)—, R^(a)—O—CS—N(R^(b))—Y^(a)—,R^(a)—N(R^(b))—CS—O—Y^(a)—, R^(a)—N(R^(b))—CS—N(R^(c))—Y^(a)—,R^(a)—O—CS—O—Y^(a)—, R^(a)—S—CO—Y^(a)—, R^(a)—S—CO—N(R^(b))—Y^(a)—,R^(a)—N(R^(b))—CO—S—Y^(a)—, R^(a)—S—CO—O—Y^(a)—, R^(a)—O—CO—S—Y^(a)—,R^(a)—S—CO—S—Y^(a)—, R^(a)—S—CS—Y^(a)—, R^(a)—CS—S—Y^(a)—,R^(a)—S—CS—N(R^(b))—Y^(a)—, R^(a)—N(R^(b))—CS—S—Y^(a)—,R^(a)—S—CS—O—Y^(a)—, R^(a)—O—CS—S—Y^(a)—, wherein R^(a) being a hydrogenatom, a C₁-C₆ alkyl, a C₂-C₆ alkenyl or a C₂-C₆ alkynyl group; R^(b)being a hydrogen atom, a C₁-C₆ alkyl, a C₂-C₆ alkenyl or a C₂-C₆ alkynylgroup; R^(c) being a hydrogen atom, a C₁-C₆ alkyl, a C₂-C₆ alkenyl or aC₂-C₆ alkynyl group; R^(d) being a hydrogen atom, a C₁-C₆ alkyl, a C₂-C₆alkenyl or a C₂-C₆ alkynyl group and Y^(a) being a direct bond, a C₁-C₆alkylene, a C₂-C₆ alkenylene or a C₂-C₆ alkynylene group, wherein eachheteroalkyl group contains at least one carbon atom and one or morehydrogen atoms may be replaced by fluorine or chlorine atoms. Preferredexamples of heteroalkyl groups are groups of formulae: R^(a)—O—Y^(a)—,R^(a)—S—Y^(a)—, R^(a)—SO—Y^(a)—, R^(a)—SO₂—Y^(a)—,R^(a)—N(R^(b))—SO₂—Y^(a)—, R^(a)—SO₂—N(R^(b))—Y^(a)—,R^(a)—N(R^(b))—Y^(a)—, R^(a)—CO—Y^(a)—, R^(a)—O—CO—Y^(a)—,R^(a)—CO—N(R^(b))—Y^(a)—, R^(a)—N(R^(b))—CO—Y^(a)—,R^(a)—O—CO—N(R^(b))—Y^(a)—, R^(a)—N(R^(b))—CO—O—Y^(a)—,R^(a)—N(R^(b))—CO—N(R^(c))—Y^(a)—, R^(a)—O—CO—O—Y^(a)— andR^(a)—N(R^(b))—C(═NR^(d))—N(R^(c))—Y^(a)—.

Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy,ethoxy, n-propyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl,ethoxymethyl, —CH₂CH₂OH, —CH₂OH, methoxyethyl, 1-methoxyethyl,1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino,propylamino, isopropylamino, dimethylamino, diethylamino,isopropyl-ethylamino, methylamino methyl, ethylamino methyl,diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, enolether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl,butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy,acetylamino or propionylamino, carboxymethyl, carboxyethyl orcarboxypropyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. Furtherexamples of heteroalkyl groups are nitrile, isonitrile, cyanate,thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

The expression cycloalkyl refers to a saturated or partially unsaturated(for example, a cycloalkenyl group) cyclic group that contains one ormore rings (preferably 1 or 2), and contains from 3 to 14 ring carbonatoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbonatoms. The expression cycloalkyl refers furthermore to groups in whichone or more hydrogen atoms have been replaced by fluorine, chlorine,bromine or iodine atoms or by OH, ═O, SH, ═S, NH₂, ═NH, N₃ or NO₂groups, thus, for example, cyclic ketones such as, for example,cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specificexamples of cycloalkyl groups are a cyclopropyl, cyclobutyl,cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl,cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline,cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group.Preferably, the expression cycloalkyl refers to a saturated cyclic groupthat contains one or more rings (preferably 1 or 2), and from 3 to 14ring carbon atoms, especially preferably from 3 to 10 (more especiallypreferably 3, 4, 5, 6 or 7) ring carbon atoms.

The expression heterocycloalkyl refers to a cycloalkyl group as definedabove in which one or more (preferably 1, 2, 3 or 4) ring carbon atomshave been replaced by an oxygen, nitrogen, silicon, selenium, phosphorusor sulfur atom (preferably by an oxygen, sulfur or nitrogen atom). Aheterocycloalkyl group has preferably 1 or 2 ring(s) containing from 3to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected fromC, O, N and S). The expression heterocycloalkyl refers furthermore togroups that may be substituted by one or more fluorine, chlorine,bromine or iodine atoms or by one or more OH, ═O, SH, ═S, NH₂, ═NH, N₃or NO₂ groups. Examples are a piperidyl, prolinyl, imidazolidinyl,piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl,tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or2-pyrazolinyl group and also lactames, lactones, cyclic imides andcyclic anhydrides.

The expression alkylcycloalkyl refers to groups that contain bothcycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance withthe above definitions, for example alkylcyclo-alkyl, cycloalkylalkyl,alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. Analkylcycloalkyl group preferably contains a cycloalkyl group thatcontains one or two rings having from 3 to 10 (especially 3, 4, 5, 6 or7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups(especially alkyl groups) having 1 or 2 to 6 carbon atoms.

The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups asdefined above in which one or more (preferably 1, 2, 3, 4 or 5) carbonatoms have been replaced by an oxygen, nitrogen, silicon, selenium,phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogenatom). A heteroalkylcycloalkyl group preferably contains 1 or 2 ringshaving from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one ortwo alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl orheteroalkyl groups) having from 1 or 2 to 6 carbon atoms. Examples ofsuch groups are alkylheterocycloalkyl, alkylheterocycloalkenyl,alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl,heteroalkylheterocycloalkyl and hetero-alkylheterocycloalkenyl, thecyclic groups being saturated or mono-, di- or tri-unsaturated.

The expression aryl refers to an aromatic group that contains one ormore rings and from 5 or 6 to 14 ring carbon atoms, preferably from 5 or6 to 10 (especially 6) ring carbon atoms. The expression aryl refersfurthermore to groups in which one or more hydrogen atoms have beenreplaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH,NH₂, N₃ or NO₂ groups. Examples are the phenyl, naphthyl, biphenyl,2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.

The expression heteroaryl refers to an aromatic group that contains oneor more rings and from 5 to 14 ring atoms, preferably from 5 to 10(especially 5 or 6 or 9 or 10) ring atoms (preferably selected from O,S, N and C), and contains one or more (preferably 1, 2, 3, 4 or 5)oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S orN). The expression heteroaryl refers furthermore to groups in which oneor more hydrogen atoms have been replaced by fluo-rine, chlorine,bromine or iodine atoms or by OH, SH, N₃, NH₂ or NO₂ groups. Examplesare pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl),phenylpyrrolyl (e.g. 3-phenylpyrrolyl), thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,thiadiazolyl, indolyl,indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl,pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl,acridinyl, pyrimidyl, 2,3-bifuryl, pyrazolyl (e.g. 3-pyrazolyl) andisoquinolinyl groups.

The expression aralkyl refers to groups containing both aryl and alsoalkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with theabove definitions, such as, for example, aryl-alkyl, arylalkenyl,arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl andalkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene,xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene,1H-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl,cumene, cyclohexylphenyl, fluorene and indane. An aralkyl grouppreferably contains one or two aromatic ring systems (1 or 2 rings)containing from 6 to 10 carbon atoms and one or two alkyl, alkenyland/or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/orone or two cycloalkyl groups containing 5 or 6 ring carbon atoms.

The expression heteroaralkyl refers to an aralkyl group as defined abovein which one or more (preferably 1, 2, 3 or 4) carbon atoms have beenreplaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron orsulfur atom (preferably oxygen, sulfur or nitrogen), that is to say togroups containing both aryl or heteroaryl, respectively, and also alkyl,alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/orheterocycloalkyl groups in accordance with the above definitions. Aheteroaralkyl group preferably contains one or two aromatic ring systems(1 or 2 rings) containing from 5 or 6 to 10 ring carbon atoms and one ortwo alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbonatoms and/or one or two cycloalkyl groups containing 5 or 6 ring carbonatoms, wherein 1, 2, 3, 4, 5 or 6 of these carbon atoms have beenreplaced by oxygen, sulfur or nitrogen atoms.

Examples are arylheteroalkyl, arylheterocycloalkyl,arylheterocycloalkenyl, arylalkyl-heterocycloalkyl,arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl,arylalkylhetero-cycloalkenyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl,heteroarylcycloalkenyl, heteroarylheterocycloalkyl,hetero-arylheterocycloalkenyl, heteroarylalkylcycloalkyl,heteroarylalkylheterocycloalkenyl, hetero-arylheteroalkylcycloalkyl,heteroarylheteroalkylcycloalkenyl andheteroarylheteroalkylhetero-cycloalkyl groups, the cyclic groups beingsaturated or mono-, di- or tri-unsaturated. Specific examples are atetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl,4-methylpyridino, 2-, 3-or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or4-carboxyphenylalkyl group.

The term halogen or halogen atom refers to F, Cl, Br or I.

The expression “optionally substituted” preferably refers to groups inwhich one, two, three or more hydrogen atoms may have been replaced byfluorine, chlorine, bromine or iodine atoms or by OH, ═O, SH, ═S, NH₂,═NH, N₃ or NO₂ groups. This expression refers furthermore to groups thatmay be substituted by one, two, three or more (preferably unsubstituted)C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ heteroalkyl, C₃-C₁₈cycloalkyl, C₂-C₁₇ heterocycloalkyl, C₄-C₂₀ alkylcycloalkyl, C₂-C₁₉heteroalkylcycloalkyl, C₆-C₁₈ aryl, C₁-C₁₇ heteroaryl, C₇-C₂₀ aralkyl orC₂-C₁₉ heteroaralkyl groups. This expression refers furthermoreespecially to groups that may be substituted by one, two, three or more(preferably unsubstituted) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ heteroalkyl, C₃-C₁₀ cycloalkyl, C₂-C₉ heterocycloalkyl, C₇-C₁₂alkylcycloalkyl, C₂-C₁₁ heteroalkylcycloalkyl, C₆-C₁₀ aryl, C₁-C₉heteroaryl, C₇-C₁₂ aralkyl or C₂-C₁₁ heteroaralkyl groups.

If a substituent contains a ring, this ring may be bonded to therespective substituted group via a single or double bond (especially asingle bond) or, if the substituted group also contains a ring, the ringof the substituent may also be annulated to the ring of the substitutedgroup.

Preferred substituents are F, Cl, Br, I, OH, ═O, NH₂, NO₂, C₁₋₄ alkyl(e.g. —CH₃, CF₃), C₁₋₄ heteroalkyl (e.g. —CN, —OMe), cyclopropyl andSO₂NH₂.

Especially preferred substituents are F, Cl, Br, OH, ═O, NH₂, CH₂NH₂,NO₂, Me, Ethyl, NMe₂, NHMe, CONH₂, OMe, OCF₃, CN and CF₃. The mostpreferred substituents are F and Cl.

According to a preferred embodiment, all alkyl, alkenyl, alkynyl,heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaralkyl groupsdescribed herein may optionally be substituted.

When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl groupcontains more than one ring, these rings may be bonded to each other viaa single or double bond or these rings may be annulated.

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I), (II) or (III) asdefined herein or a pharmaceutically acceptable ester, prodrug, hydrate,solvate or salt thereof, optionally in combination with apharmaceutically acceptable carrier.

It is a further object of the present invention to provide a compound offormula (I), (II) or (III) as defined herein or a pharmaceuticalcomposition as defined herein for the preparation of a medicament forthe treatment of one or more diseases associated with arginase activity.

Preferably the compounds of the present invention may be used for thetreatment and/or prevention of asthma (e.g. acute and chronic asthma),COPD, allergic rhinitis, erectile dysfunction, pulmonary hypertension,hypertension, T cell dysfunction, atherosclerosis, renal disease,ischemia reperfusion injury, neurodegenerative diseases, wound healing,inflammatory diseases, fibrotic diseases and cancer.

A therapeutically effective amount of a compound in accordance with thisinvention means an amount of compound that is effective to prevent,alleviate or ameliorate symptoms of disease or prolong the survival ofthe subject being treated. Determination of a therapeutically effectiveamount is within the skill in the art.

The therapeutically effective amount or dosage of a compound accordingto this invention can vary within wide limits and may be determined in amanner known in the art. Such dosage may be adjusted to the individualrequirements in each particular case including the specific compoundbeing administered, the route of administration, the condition beingtreated, as well as the patient being treated.

Examples of pharmacologically acceptable salts of sufficiently basiccompounds of formula (I), (II) or (III) are salts of physiologicallyacceptable mineral acids like hydrochloric, hydrobromic, sulfuric andphosphoric acid; or salts of organic acids like methanesulfonic,p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic,fumaric, maleic and salicylic acid. Further, a sufficiently acidiccompound of formula (I), (II) or (III) may form alkali or earth alkalimetal salts, for example sodium, potassium, lithium, calcium ormagnesium salts; ammonium salts; or organic base salts, for examplemethylamine, dimethylamine, trimethylamine, triethylamine,ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine,morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all ofwhich are also further examples of salts of formula (I), (II) or (III).Compounds of formula (I), (II) or (III) may be solvated, especiallyhydrated. The hydratization/hydration may occur during the process ofproduction or as a consequence of the hygroscopic nature of theinitially water free compounds of formula (I), (II) or (III). Thesolvates and/or hydrates may e.g. be present in solid or liquid form.

It should be appreciated that certain compounds of formula (I), (II) or(III) or may have tautomeric forms from which only one might bespecifically mentioned or depicted in the following description,different geometrical isomers (which are usually denoted as cis/transisomers or more generally as (E) and (Z) isomers) or different opticalisomers as a result of one or more chiral carbon atoms (which areusually nomenclatured under the Cahn-Ingold-Prelog or R/S system). Allthese tautomeric forms, geometrical or optical isomers (as well asracemates and diastereomers) and polymorphous forms are included in theinvention. Since the compounds of formula (I), (II) or (III) may containasymmetric C-atoms, they may be present either as achiral compounds,mixtures of diastereomers, mixtures of enantiomers or as optically purecompounds. The present invention comprises both all pure enantiomers andall pure diastereomers, and also the mixtures thereof in any mixingratio.

The therapeutic use of compounds according to formula (I), (II) or(III), their pharmacologically acceptable salts, solvates and hydrates,respectively, as well as formulations and pharmaceutical compositionsalso lie within the scope of the present invention.

The pharmaceutical compositions according to the present inventioncomprise at least one compound of formula (I), (II) or (III) as anactive ingredient and, optionally, carrier substances and/or adjuvants.

The present invention also relates to pro-drugs which are composed of acompound of formula (I), (II) or (III) and at least onepharmacologically acceptable protective group which will be cleaved offunder physiological conditions, such as an alkoxy-, arylalkyloxy-,acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-,2-aryl- or 2-arylalkyl-oxycarbonyl-2-alkylidene ethyl group or anacyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl oracetyloxy or, especially for a compound of formula (I), (II) or (III),carrying a hydroxy group (—OH): a sulfate, a phosphate (—OPO₃ or—OCH₂OPO₃) or an ester of an amino acid.

Preferably, the present invention also relates to a prodrug, abiohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer,stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate,biohydrolyzable ether, physiologically functional derivative,atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixtureof diastereomers, chemically protected form, affinity reagent, complex,chelate and a stereoisomer of the compounds of formula (I), (II) or(III).

As used herein, the term pharmaceutically acceptable ester especiallyrefers to esters which hydrolyze in vivo and include those that breakdown readily in the human body to leave the parent compound or a saltthereof. Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

As mentioned above, therapeutically useful agents that contain compoundsof formula (I), (II) or (III), their solvates, salts or formulations arealso comprised in the scope of the present invention. In general,compounds of formula (I), (II) or (III) will be administered by usingthe known and acceptable modes known in the art, either alone or incombination with any other therapeutic agent.

For oral administration such therapeutically useful agents can beadministered by one of the following routes: oral, e.g. as tablets,dragees, coated tablets, pills, semisolids, soft or hard capsules, forexample soft and hard gelatine capsules, aqueous or oily solutions,emulsions, suspensions or syrups, parenteral including intravenous,intramuscular and subcutaneous injection, e.g. as an injectable solutionor suspension, rectal as suppositories, by inhalation or insufflation,e.g. as a powder formulation, as microcrystals or as a spray (e.g.liquid aerosol), transdermal, for example via an transdermal deliverysystem (TDS) such as a plaster containing the active ingredient orintranasal. For the production of such tablets, pills, semisolids,coated tablets, dragees and hard, e.g. gelatine, capsules thetherapeutically useful product may be mixed with pharmaceutically inert,inorganic or organic excipients as are e.g. lactose, sucrose, glucose,gelatine, malt, silica gel, starch or derivatives thereof, talc,stearinic acid or their salts, dried skim milk, and the like. For theproduction of soft capsules one may use excipients as are e.g.vegetable, petroleum, animal or synthetic oils, wax, fat, polyols. Forthe production of liquid solutions, emulsions or suspensions or syrupsone may use as excipients e.g. water, alcohols, aqueous saline, aqueousdextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins,vegetable, petroleum, animal or synthetic oils. Especially preferred arelipids and more preferred are phospholipids (preferred of naturalorigin; especially preferred with a particle size between 300 to 350 nm)preferred in phosphate buffered saline (pH=7 to 8, preferred 7.4). Forsuppositories one may use excipients as are e.g. vegetable, petroleum,animal or synthetic oils, wax, fat and polyols. For aerosol formulationsone may use compressed gases suitable for this purpose, as are e.g.oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agentsmay also contain additives for conservation, stabilization, e.g. UVstabilizers, emulsifiers, sweetener, aromatizers, salts to change theosmotic pressure, buffers, coating additives and antioxidants.

In general, in the case of oral or parenteral administration to adulthumans weighing approximately 80 kg, a daily dosage of about 10 mg toabout 10,000 mg, preferably from about 20 mg to about 1,000 mg, shouldbe appropriate, although the upper limit may be exceeded when indicated.The daily dosage can be administered as a single dose or in divideddoses, or for parenteral administration, it may be given as continuousinfusion or subcutaneous injection.

EXAMPLES Example 1: Pent-4-en-1-yl acetate

To a solution of 1-Pentenol (20 g, 232 mmol) in CH₂Cl₂ (100 mL) wasadded Et₃N (65 mL, 464 mmol) and DMAP (0.68 g, 5.5 mmol). The mixturewas cooled to 0° C. using an ice bath and acetic anhydride (25mL, 255mmol) was added drop wise. The mixture was stirred at RT for 1 hour. Themixture was diluted using CH₂Cl₂ (100 mL) and washed with water (2×100mL), 1N aqueous HCl (100 mL), brine (100 mL). The organic layer wascollected and dried over MgSO4, filtered and concentrated under reducedpressure to obtain the pent-4-en-1-yl acetate (27 g, 90% yield) as acolorless oil.

¹H NMR (400 MHz, Chloroform-d) δ5.83-5.78 (m, 1H), 5.06-4.90 (m, 2H),4.07 (t, J=6.7 Hz, 2H), 2.15-2.10 (m, 2H), 2.04 (d, J=3.2 Hz, 3H),1.76-1.70 (m, 2H); ¹³C NMR (126 MHz, CDCl3) δ171.1, 137.6, 115.4, 64.0,30.1, 28.0, 21.0.

Example 2: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl acetate

To a solution of the chloro(1,5-cyclooctadiene)iridium(I)dimer (395 mg,0.6 mmol) and ethylenebis(diphenylphosphine) (492 mg, 1.2 mmol) in 50 mLwas added the Pent-4-en-1-yl acetate (5.5 g, 43 mmol, obtained inexample 1) and pinacolborane (6.0 g, 47 mmol). The mixture was stirredfor 20 h. and then quenched using 10 mL MeOH, washed with water (2×50mL), brine (50 mL), dried over MgSO4, filtered and concentrated underreduced pressure to obtain the crude product 11.5 g crude product as ayellow oil. The crude product was purified by flash chromatographyyielding 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl acetate(7.8 g, 83% yield) of as a colorless oil.

¹H NMR (500 MHz, CDCl3) δ4.06 (t, J=6.8 Hz, 2H), 2.07-2.01 (m, 3H),1.68-1.59 (m, 2H), 1.48-1.42 (m, 2H), 1.39-1.35 (m, 2H), 1.26-1.25 (s,12H), 0.79 (t, J=7.7 Hz, 2H) ppm; ¹³C NMR (126 MHz, CDCl3) δ83.1, 64.8,28.7, 28.6, 25.0, 24.7, 23.8, 21.1.

Example 3: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentan-1-ol

To a solution of the5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl acetate (11 g, 43mmol, obtained in example 2) in EtOH (150 mL) was added powdered K₂CO₃(11.3 g, 82 mmol). After 20 hours of stirring at RT, the solvent wasremoved under reduced pressure. The resultant mixture was re-dissolvedin EtOAc (100 mL), washed with water (100 mL), brine (100 mL), driedover MgSO₄, filtered and concentrated under reduced pressure to obtain13 g crude product. Further purification was performed by flashchromatography to obtain 5-(4, 4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentan-1-ol (6.7 g, 77% yield) asa slightly yellow oil.

¹H NMR (500 MHz, Chloroform-d) δ3.62 (t, J=6.6 Hz, 1H), 1.59-1.54 (m,2H), 1.46-1.41 (m, 2H), 1.39-1.34 (m, 2H) 1.25 (s, 12H), 0.79 (t, J=7.6Hz, 2H); ¹³C NMR (126 MHz, Chloroform-d) 8 83.1, 64.7, 28.7, 28.5, 24.9,24.7, 23.8, 21.1.

Example 4: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal

Oxalyl chloride (3.2 mL, 38 mmol) was dissolved in CH₂Cl₂ and cooled to−78° C. DMSO (8.9 mL, 125 mmol) was dissolved in DCM (9.0 mL) and addeddrop wise. After 15 minutes of stirring, the5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentan-1-ol (6.7 g, 31mmol, obtained in example 3) was dissolved in CH₂Cl₂ (10 mL) and dropwise added to the reaction mixture and stirred for 40 minutes. Et₃N(26.2 mL, 188 mmol) was added slowly and the mixture was allowed to warmslowly to room temperature. The mixture was diluted with CH₂Cl₂ (100 mL)and poured onto ice-water (100 mL). The mixture was washed with water(2×50 mL), brine (3×50 mL), dried over MgSO4, filtered and concentratedunder reduced pressure to obtain 12 g crude product. The product5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal was afforded byflash chromatography purification yielding 4.6 g (69% yield) as aslightly yellow oil.

Example 5: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal

To a stirred solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentan-1-ol (5 g, 21.91mmol, obtained in example 3) was dissolved in CH₂Cl₂ (50 mL) was addedpyridinium chlorochromate (PCC) (7.08 g, 32.87 mmol) in portion wiseover the period of 0.5 h. The resulted reaction mixture was furtherstirred for 1 h at room temperature. Reaction mixture was diluted withDCM (50 mL) and filtered through pad of silica and the solvent wasremoved under reduced pressure to obtain5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal (4.0 g). ¹ H NMR(500 MHz, Chloroform-d) δ9.76 (s, 1H), 2.44-2.40 (m, 2H), 1.68-1.61 (m,2H), 1.50-1.43 (m, 2H), 1.25 (s, 12H), 0.82-0.78 (m, 2H) ppm; ¹³C NMR(126 MHz, Chloroform-d) δ203.1, 83.1, 83.0, 43.9, 24.9, 24.8, 24.7,23.8.

Examples 6 and 7 were Prepared in Analogous Manner of Example 5,Starting from Appropriates Intermediates

Example No. IUPAC name 66-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanal 74-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butanal

Example 8: (1-(4-chlorobenzyl)piperidin-4-yl)methanamine hydrochloride

To a stirred solution of tert-butyl (piperidin-4-ylmethyl)carbamate (1.0g, 4.67 mmol) and 4-chlorobenzaldehyde (0.85 g, 6.07 mmol) indichloroethane (10 mL) was added glacial acetic acid (0.03 mL, 0.467mmol) and stirred for 1.5 h. Subsequently, sodium triacetoxyborohydride(2.47 g, 11.67 mmol) was added in portions over the period of 1 h. andthe reaction mixture was further stirred for 18 h. To the reactionmixture was added DCM (20 mL) and aqueous saturated sodium bicarbonatesolution (15 mL). The organic layer was separated and washed with brine(20 mL), dried over MgSO4, filtered and concentrated under reducedpressure to obtain the tert-butyl((1-(4-chlorobenzyl)piperidin-4-yl)methyl)carbamate (1.05 g). ¹H NMR(500 MHz, Chloroform-d) δ7.30-7.19 (m, 4H), 4.58 (br. s, 1H), 3.43 (s,2H), 3.01 (t, J=6.4 Hz, 2H), 2.84 (dt, J=11.9, 3.3 Hz, 2H), 1.92 (td,J=11.6, 2.5 Hz, 2H), 1.69-1.60 (m, 2H), 1.43 (s, 9H), 1.25 (tt, J=11.9,6.0 Hz, 2H); MS (EI) m/z: 339.2 (M+H)⁺ The tert-butyl((1-(4-chlorobenzyl)piperidin-4-yl)methyl)carbamate (1.0 g) wasdissolved in 1,4-dioxane (3.0 mL) and 4N HCl/dioxane (3.0 mL) was added.The reaction mixture was further stirred for 16 h. The solvent wasremoved under reduced pressure and to the residue was added diethylether (10 mL) and the solid product(1-(4-chlorobenzyl)piperidin-4-yl)methanamine hydrochloride (1.05 g) wascollected by filtration.

Example 9: N-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)formamide

To a stirred suspension of (1-(4-chlorobenzyl)piperidin-4-yl)methanaminehydrochloride (1.0 g) in ethyl formate (10 mL) was added triethyl amine(2.0 mL) and the resulted reaction mixture was refluxed for 16 h. Thesolvent was removed under reduced pressure and the residue was dissolvedin ethyl acetate (20 mL). The organic layer was washed with H₂O (10 mL)and brine (10 mL), dried over MgSO4, filtered and concentrated underreduced pressure to obtain theN-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)formamide (0.45 g) as a paleyellow solid. ¹H NMR (500 MHz, Chloroform-d) δ8.18 (s, 1H), 7.31-7.19(m, 4H), 5.65 (s, 1H), 3.44 (s, 2H), 3.19 (t, J=6.5 Hz, 2H), 2.85 (dt,J=12.1, 3.6 Hz, 2H), 1.93 (td, J=11.7, 2.5 Hz, 2H), 1.73-1.63 (m, 2H),1.60-1.47 (m, 1H), 1.35-1.17 (m, 2H); MS (EI) m/z: 267.2 (M+H)⁺.

Example 9: N-(2-aminoethyl)-4-chlorobenzamide hydrochloride

To a cooled solution of tert-butyl (2-aminoethyl)carbamate (1.5 g, 9.36mmol) and triethylamine (2.60 mL, 18.72 mmol) in dichloromethane (20 mL)was added dropwise 4-chlorobenzoyl chloride (1.31 mL, 10.30 mmol) andstirred for 2.0 h. Reaction mixture was quenched by addition of H₂O andthe organic layer was separated and washed with brine (10 mL), driedover MgSO4, filtered and concentrated under reduced pressure to obtainthe tert-butyl (2-(4-chlorobenzamido)ethyl)carbamate (2.3 g).MS (EI)m/z: 299.2 (M+H)⁺. The tert-butyl (2-(4-chlorobenzamido)ethyl)carbamate(2.3 g) was dissolved in 1,4-dioxane (10.0 mL) and 4N HCl/dioxane (10mL) was added. The reaction mixture was further stirred for 16 h. Thesolvent was removed under reduced pressure and to the residue diethylether (10 mL) was added and the productN-(2-aminoethyl)-4-chlorobenzamide hydrochloride was collected byfiltration as a white solid (2.0 g).

Example 10: 4-chloro-N-(2-formamidoethyl)benzamide

To a stirred suspension of (N-(2-aminoethyl)-4-chlorobenzamidehydrochloride (2.3 g) in ethyl formate (20 mL) was added triethyl amine(3.0 mL) and the resulted reaction mixture was refluxed for 16 h. Thesolvent was removed under reduced pressure and the residue was dissolvedin ethyl acetate (30 mL). The organic layer was washed with H₂O (10 mL)and brine (10 mL), dried over MgSO4, filtered and concentrated underreduced pressure to obtain the 4-chloro-N-(2-formamidoethyl)benzamide(2.0 g).

¹ H NMR (500 MHz, Chloroform-d) δ8.22 (s, 1H), 7.81 (d, J=8.5 Hz, 2H),7.64 (br. s, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.04 (br. s, 1H), 3.63-3.57(m, 2H), 3.57-3.51 (m, 2H); MS (EI) m/z: 227.1 (M+H)⁺.

Examples 11-58 were either obtained from Corresponding Commercial Sourceor Prepared as per Literature Methods

Examples 59a-59t were either obtained from Corresponding CommercialSource or Prepared as per Literature Methods

Example 60: N-benzyl-2-isocyanoacetamide

Synthesized as described in Synthesis 2016, 48, 3701-3712.

Examples 61-121 were Prepared in Analogous Manner of Example 60

Example 127: N-benzyl-3-isocyanopropanamide

Synthesized as described in Synthesis 2016, 48, 3701-3712 by stirringmethyl 3-isocyanopropanoate (1.0 mmol) and benzyl amine (1.0 mmol) atroom temperature for 48 h. ¹H NMR (500 MHz, Chloroform-d) δ7.38-7.32 (m,2H), 7.32-7.27 (m, 3H), 5.96 (s, 1H), 4.46 (d, J=5.7 Hz, 2H), 3.74 (tt,J=8.5, 4.7, 1.9 Hz, 2H), 2.58 (tt, J=6.8, 2.0 Hz, 2H).

Examples 128a-128c were Prepared in Analogous Manner of Preparation 127

Example 129:1-(1-(4-chlorobenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine

To a stirred solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal (0.25 g, 1.17mmol) in methanol (2.0 mL) was added tritylamine (0.297 g, 1.17 mmol)and stirred for 0.5 h. Subsequently 1-chloro-4-(isocyanomethyl)benzene(0.16 mL, 1.17 mmol) and azidotrimethylsilane (0.15 mL, 1.17 mmol) wereadded and further stirred for 16 h. The solvent was removed underreduced pressure and the residue was purified using flash chromatographyto provide1-(1-(4-chlorobenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-l-amine(0.45 g).

¹H NMR (500 MHz, Chloroform-d) δ7.41-7.34 (m, 6H), 7.30-7.25 (m, 2H),7.24-7.14 (m, 9H), 6.98 (d, J=8.4 Hz, 2H), 4.97 (q, J=252.5, 15.5 Hz,2H), 3.97 (td, J=7.8, 5.1 Hz, 1H), 2.86 (d, J=8.0 Hz, 1H), 1.60-1.50 (m,1H), 1.44-1.32 (m, 1H), 1.21 (s, 12H), 1.20-1.07 (m, 2H), 0.91 (tdd,J=20.3, 12.4, 8.2 Hz, 2H), 0.55 (td, J=7.5, 1.7 Hz, 2H); LC-MS (EI) m/z:670.3 (M+Na)⁺.

Example 130:1-(1-(2-fluoro-5-nitrophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine

To a stirred solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal (0.25 g, 1.17mmol) in methanol (2.0 mL) was added tritylamine (0.297 g, 1.17 mmol)and stirred for 0.5 h. Subsequently 1-fluoro-2-isocyano-4-nitrobenzene(0.195g, 1.17 mmol) and azidotrimethylsilane (0.15 mL, 1.17 mmol) wereadded and further stirred for 16 h. The solvent was removed underreduced pressure and the residue was purified using flash chromatographyto provide1-(1-(2-fluoro-5-nitrophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine(0.41 g).

¹H NMR (500 MHz, Chloroform-d) δ8.47 (dd, J=8.9, 2.5 Hz, 1H), 7.52 (s,1H), 7.42 (d, J=8.9 Hz, 1H), 7.26-7.20 (m, 6H), 7.20-7.14 (m, 9H),3.88-3.77 (m, 1H), 2.54 (d, J=5.6 Hz, 1H), 1.64-1.52 (m, 1H), 1.46-1.35(m, 1H), 1.19 (s, 12H), 1.16-0.94 (m, 4H), 0.58 (t, J=7.5 Hz, 2H); LC-MS(EI) m/z: 685.3 (M+Na)⁺.

Example 131: Methyl2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetate

To a stirred solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal (0.25 g, 1.17mmol) in methanol (2.0 mL) was added tritylamine (0.297 g, 1.17 mmol)and stirred for 0.5 h. Subsequently methyl 2-isocyanoacetate (0.1 mL,1.17 mmol) and azidotrimethylsilane (0.15 mL, 1.17 mmol) were added andfurther stirred for 16 h. The solvent was removed under reduced pressureand the residue was purified using flash chromatography to providemethyl 2-(5-(5 -(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetate(0.42 g).

¹H NMR (500 MHz, Chloroform-d) δ7.35-7.29 (m, 6H), 7.24-7.13 (m, 9H),4.69 (q, J=348.1, 17.6 Hz, 2H), 4.05-3.97 (m, 1H), 3.72 (s, 3H), 2.85(d, J=6.6 Hz, 1H), 1.84 (dq, J=13.3, 8.0 Hz, 1H), 1.69 (dtd, J=13.1,7.7, 5.1 Hz, 1H), 1.34-1.28 (m, 2H), 1.21 (s, 12H), 1.19-1.13 (m, 2H),0.69 (t, J=7.8 Hz, 2H); LC-MS (EI) m/z: 618.3 (M+Na)⁺.

Example 132: methyl4-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)butanoate

The compound of example 132 was obtained by similar method described inexample 131. ¹H NMR (500 MHz, Chloroform-d) δ7.41-7.36 (m, 6H),7.22-7.16 (m, 6H), 7.16-7.10 (m, 3H), 3.92 (td, J=8.1, 4.8 Hz, 1H), 3.83(dt, J=14.4, 7.4 Hz, 1H), 3.77-3.68 (m, 1H), 3.66 (s, 3H), 2.95 (d,J=8.2 Hz, 1H), 2.33 (td, J=6.9, 1.6 Hz, 2H), 2.05-1.95 (m, 2H),1.93-1.83 (m, 1H), 1.72-1.61 (m, 1H), 1.38-1.27 (m, 2H), 1.20 (s, 12H),1.16-1.03 (m, 2H), 0.69 (dd, J=8.5, 7.1 Hz, 2H); LC-MS (EI) m/z: 646.3(M+Na)⁺.

Example 133:N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)pentan-1-amine

To a stirred solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal (0.25 g, 1.17mmol) in methanol (2.0 mL) was added methyl amine (40% solution inmethanol, 0.09 mL, 1.17 mmol) and stirred for 0.5 h. Subsequentlytert-Octylisocyanide (0.2 mL, 1.17 mmol) and azidotrimethylsilane (0.15mL, 1.17 mmol) were added and further stirred for 16 h. The solvent wasremoved under reduced pressure and the residue was purified using flashchromatography to provideN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)pentan-1-amine(0.2 g).

¹H NMR (500 MHz, Chloroform-d) δ4.08 (dd, J=8.0, 5.2 Hz, 1H), 2.30 (s,3H), 1.97 (q, J=27.3, 15.4 Hz, 2H), 1.89-1.75 (m, 7H), 1.61-1.52 (m,1H), 1.50-1.30 (m, 4H), 1.22 (s, 11H), 0.84 (s, 9H), 0.77 (t, J=7.6 Hz,2H); LC-MS (EI) m/z: 430.3 (M+Na)⁺.

Example 134:1-(1-benzyl-1H-tetrazol-5-yl)-N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentan-1-amine

The compound of example 134 was obtained by similar method described inexample 133. LC-MS (EI) m/z: 514.3 (M+Na)⁺.

Example135:N-(4-methoxybenzyl)-2-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)hex-5-en-2-amine

To a stirred solution of hex-5-en-2-one (0.25g, 2.54 mmol) in methanol(1.0 mL) was added (4-methoxyphenyl)methanamine (0.32 mL, 2.54 mmol) andstirred for 1 h. Subsequently tert-Octylisocyanide (0.445 mL, 2.54 mmol)and azidotrimethylsilane (0.33 mL, 2.54 mmol) were added and furtherstirred for 16 h. The solvent was removed under reduced pressure and theresidue was purified using flash chromatography to provideN-(4-methoxybenzyl)-2-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)hex-5-en-2-amine(0.75 g).

¹H NMR (500 MHz, Chloroform-d) δ7.24 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6Hz, 2H), 5.82 (ddt, J=16.9, 10.1, 6.5 Hz, 1H), 5.01 (dd, J=17.1, 1.7 Hz,1H), 4.96 (dd, J=10.2, 1.7 Hz, 1H), 3.79 (s, 3H), 3.68 (dd, J=27.4, 11.5Hz, 2H), 2.36 (ddd, J=13.7, 11.7, 4.8 Hz, 1H), 2.23 (ddd, J=13.7, 11.6,4.9 Hz, 1H), 2.13-2.06 (m, 2H), 1.97 (dd, J=27.7, 10.3 Hz, 6H), 1.87 (d,J=15.0 Hz, 1H), 1.81-1.74 (m, 1H), 1.72 (s, 3H), 0.65 (s, 9H); LC-MS(EI) m/z: 422.3 (M+Na)⁺.

Example136:N-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)hexan-2-amine

To a solution of the chloro(1,5-cyclooctadiene)iridium(I)dimer (4.7 mg,0.6 mmol) and ethylenebis(diphenylphosphine) (5.5 mg, 1.2 mmol) in 1.5mL DCM was addedN-(4-methoxybenzyl)-2-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)hex-5-en-2-amine(0.2 g, 0.5 mmol) and pinacolborane (0.07 mL, 0.55 mmol). The reactionmixture was stirred for 20 hours and then quenched using 0.2 mL MeOH,washed with water (2×5 mL), brine (5 mL), dried over MgSO4, filtered andconcentrated under reduced pressure to obtain the crude product. Thecrude product was purified by flash chromatography yieldingN-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(1-(2,4,4-trimethylpen tan-2-yl)-1H-tetrazol-5-yl)hexan-2-amine (0.205 g) of as a whitesolid.

¹H NMR (500 MHz, Chloroform-d) δ7.24 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6Hz, 2H), 3.79 (s, 3H), 3.65 (q, J=43.5, 11.7 Hz, 2H), 2.24-2.11 (m, 2H),2.06 (d, J=14.9 Hz, 1H), 1.97 (s, 3H), 1.97 (s, 3H), 1.91 (d, J=15.0 Hz,1H), 1.73 (s, 3H), 1.53 -1.38 (m, 2H), 1.37 -1.25 (m, 1H), 1.21 (d,J=2.3 Hz, 12H), 1.02-0.91 (m, 1H), 0.77 (t, J=7.8 Hz, 2H), 0.66 (s, 9H);LC-MS (EI) m/z: 550.5 (M+Na)⁺.

Example 137a:N-phenethyl-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide(Major Product) Example 137b:N-((1-phenethyl-1H-tetrazol-5-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(tritylamino)hexanamide(Minor Product)

To a stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal (0.2 g, 0.94 mmol) in methanol (2.0 mL) was added tritylamine(0.24 g, 0.94 mmol) and stirred for 0.5 h. Subsequently2-isocyano-N-phenethylacetamide (0.176 g, 0.94 mmol) andazidotrimethylsilane (0.18 mL, 1.41 mmol) were added and further stirredfor 16 h. The solvent was removed under reduced pressure and the residuewas purified using flash chromatography to provideN-phenethyl-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide(Major product, 0.450 g) and N-((1-phenethyl-1H-tetrazol-5-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(tritylamino)hexanamide(Minor product, 0.030 g).

(Major desired product) ¹H NMR (500 MHz, Chloroform-d) δ7.39-7.30 (m,7H), 7.31-7.26 (m, 2H), 7.24-7.16 (m, 7H), 7.16-7.07 (m, 3H), 5.87 (t,J=5.8 Hz, 1H), 4.72 (d, J=16.6 Hz, 1H), 4.26 (d, J=16.6 Hz, 1H), 3.98(td, J=8.0, 5.0 Hz, 1H), 3.50-3.34 (m, 2H), 2.92 (d, J=7.5 Hz, 1H), 2.72(td, J=7.1, 2.7 Hz, 2H), 1.83 (dddd, J=13.5, 11.1, 8.4, 5.1 Hz, 1H),1.74 (ddq, J=15.2, 12.4, 7.3, 6.2 Hz, 1H), 1.35-1.25 (m, 2H), 1.20 (s,12H), 1.10 -1.02 (m, 1H), 1.02-0.92 (m, 1H), 0.65 (td, J=7.6, 2.9 Hz,2H); ¹³C NMR (126 MHz, Chloroform-d) 6 164.1, 158.4, 145.0, 138.1,128.9, 128.9, 128.8, 128.8, 128.7, 128.6, 128.0, 126.9, 126.9, 126.8,83.1, 71.6, 50.1, 48.7, 41.2, 41.1, 37.2, 35.4, 35.4, 27.5, 24.9, 23.8,10.9; LC-MS (EI) m/z: 707.4 (M+Na)⁺.

(Minor product) ¹H NMR (500 MHz, Chloroform-d) δ7.31-7.24 (m, 9H),7.23-7.18 (m, 6H), 7.18-7.12 (m, 3H), 7.01-6.95 (m, 2H), 4.59 (td,J=6.9, 2.3 Hz, 2H), 3.71 (dd, J=15.7, 6.1 Hz, 1H), 3.57 (dd, J=15.8, 6.3Hz, 1H), 3.24 (dd, J=6.7, 4.6 Hz, 1H), 3.13 (t, J=6.9 Hz, 2H), 1.69-1.53 (m, 1H), 1.37 -1.24 (m, 4H), 1.20 (s, 12H), 1.15-1.01 (m, 1H),0.66 (t, J=7.7 Hz, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ175.4, 152.4,145.3, 136.3, 128.9, 128.8, 128.8, 128.6, 128.5, 127.9, 127.9, 127.3,126.8, 82.9, 71.6, 57.5, 48.7, 36.3, 34.8, 30.6, 27.5, 24.9, 24.8, 24.0,10.9; LC-MS (EI) m/z: 707.4 (M+Na)⁺.

Example 138:6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)-N-tritylhexan-1-amine

The compound of example 138 was obtained by similar method described inexample 129 starting from6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanal (1.0 mmol),tritylamine(1.0 mmol), tert-octyl isocyanide (1.0 mmol) andazidotrimethylsilane (1.0 mmol) in methanol .

¹H NMR (500 MHz, Chloroform-d) δ7.47-7.39 (m, 6H), 7.24-7.17 (m, 6H),7.18-7.11 (m, 3H), 4.28 (dt, J=9.7, 5.1 Hz, 1H), 3.28 (d, J=8.9 Hz, 1H),1.75-1.66 (m, 2H), 1.59 (s, 2H), 1.50 (s, 3H), 1.40 (s, 3H), 1.36 -1.25(m, 3H), 1.23 (s, 12H), 1.20 -1.03 (m, 3H), 0.79 (s, 9H), 0.70 (t, J=7.8Hz, 2H); LC-MS (EI) m/z: 672.3 (M+Na)⁺.

Example 139:N-benzyl-3-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)propanamide

The compound of example 139 was obtained by similar method described inexample 129 starting from5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanal (1.0 mmol),tritylamine (1.0 mmol), 3-isocyano-N-phenethylpropanamide (1.0 mmol) andazidotrimethylsilane (1.0 mmol) in methanol.

¹H NMR (500 MHz, Chloroform-d) δ7.41-7.35 (m, 6H), 7.35-7.30 (m, 2H),7.24-7.15 (m, 8H), 7.15-7.09 (m, 3H), 5.93 (t, J=5.8 Hz, 1H), 4.46-4.31(m, 2H), 4.16-3.89 (m, 3H), 2.97 (d, J=8.3 Hz, 1H), 2.64 (td, J=7.4, 1.8Hz, 2H), 1.96-1.84 (m, 1H), 1.80-1.69 (m, 1H), 1.39 -1.27 (m, 2H), 1.18(s, 12H), 1.15-0.99 (m, 2H), 0.75-0.60 (m, 2H); LC-MS (EI) m/z: 683.3(M−H)⁺.

Example 140:1-(1-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amin

To a stirred solution ofN-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)formamide (0.188 g, 0.70mmol) in DCM (1.0 mL), trimethylamine (0.24 mL, 2.4 mmol) was added andcooled to −5° C. After 10 minutes, triphosgene (0.084 g, 0.28 mmol) inDCM (0.5 mL) was added slowly. The reaction mixture was stirred for 10minutes until the formamide was completely consumed (monitored by TLC).Afterwards, preformed Schiff's base [ prepared by mixing5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pentanal (0.1 g, 0.471mmol) and tritylamine (0.12 g, 0.471 mmol) in methanol (1.0 mL) andstirred for 30 minutes] and azidotrimethylsilane (0.1 mL, 0.471 mmol)were added and further stirred at room temperature for 16 h. The solventwas removed under reduced pressure and the residue was purified usingflash chromatography to provide1-(1-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-l-amin(0.225 g).

¹H NMR (500 MHz, Chloroform-d) δ7.42-7.35 (m, 6H), 7.30-7.24 (m, 2H),7.24-7.16 (m, 8H), 7.16-7.09 (m, 3H), 3.88 (td, J=7.6, 4.7 Hz, 1H), 3.61(dd, J=13.9, 7.1 Hz, 1H), 3.48 -3.35 (m, 3H), 2.91 (d, J=8.4 Hz, 1H),2.85-2.72 (m, 2H), 1.92-1.80 (m, 3H), 1.81-1.71 (m, 1H), 1.66 -1.53 (m,2H), 1.45 (ddq, J=37.0, 13.6, 3.9, 3.4 Hz, 2H), 1.37 -1.26 (m, 2H), 1.20(s, 12H), 1.17-1.08 (m, 1H), 0.68 (t, J=7.8 Hz, 2H); ¹³C NMR (126 MHz,Chloroform-d) δ157.7, 145.4, 137.0, 132.8, 130.4, 128.6, 128.4, 127.9,126.8, 83.0, 71.6, 62.4, 52.9, 52.9, 52.5, 48.1, 37.4, 35.8, 30.0, 30.0,29.5, 27.5, 24.9, 24.9, 24.9, 24.1, 11.0; LC-MS (EI) m/z: 767.4 (M+Na)⁺.

Example 141 to 230 were Prepared in Analogues Manner of Example 129-140from the Appropriate Intermediate that are Commercially Available orSynthesized as Above

Ex. LC-MS No. (EI)m/z: IUPAC Name 141 636.61-(1-benzyl-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine. 142 654.61-(1-(3-fluorobenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine. 143 650.61-(1-phenethyl-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine. 144 627.41-(1-cyclohexyl-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine 145 602.31-(1-(tert-butyl)-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine. 146 693.4N-benzyl-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2- (M + Na)⁺dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H- tetrazol-1-yl)acetamide.147 513.2 4-(1-(1-(2-fluoro-5-nitrophenyl)-1H-tetrazol-5- (M + Na)⁺yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pentyl)morpholine.148 752.5 1-(1-(2-morpholino-5-nitrophenyl)-1H-tetrazol-5- (M + Na)⁺yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine. 149 711.4N-(4-fluorobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 150 707.5N-((S)-1-phenylethyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 151 699.42-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- (M + Na)⁺2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)-N-(thiophen-2-ylmethyl)acetamide. 152 776.5N-(1-benzylpiperidin-4-yl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 153 643.4N-cyclopropyl-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2- (M + Na)⁺;dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H- 619.3tetrazol-1-yl)acetamide. (M − H)⁺ 154 643.4N-(2-morpholinoethyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 155 767.5N-(3,4-dimethoxyphenethyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 156 659.4N-butyl-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2- (M + Na)⁺dioxaborolan-2-yl)-1-(tritylamino)pentyl)- 1H-tetrazol-1-yl)acetamide.157 641.3 N-(prop-2-yn-1-yl)-2-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 158 762.41-(4-benzylpiperazin-1-yl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)ethanone. 159 673.41-morpholino-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2- (M + Na)⁺dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H- tetrazol-1-yl)ethanone 160657.4 1-(pyrrolidin-1-yl)-2-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)ethanone. 161 727.5N-(3-chlorobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 162 727.5N-(2-chlorobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 694.4N-(pyridin-3-ylmethyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 163 723.4N-(4-methoxybenzyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 164 741.4N-(4-chlorobenzyl)-3-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)propanamide. 165 721.4N-phenethyl-3-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)propanamide 166 646.5 methyl4-(5-(5-(4,4,5,5-tetramethyl-1,3,2- (M + Na)⁺dioxaborolan-2-yl)-1-(tritylamino)pentyl)- 1H-tetrazol-1-yl)butanoate.167 689.4 1-(1-(2-(1H-indol-3-yl)ethyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine.168 737.4 N-benzyl-N-(2-hydroxyethyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 169 707.4N-benzyl-N-methyl-2-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 170 741.5N-((S)-1-(4-chlorophenyl)ethyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 171 650.41-(1-(1-phenylethyl)-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan- 1-amine. 172 650.41-(1-((R)-1-phenylethyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine.173 650.4 1-(1-((S)-1-phenylethyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine.174 684.4 1-(1-((R)-1-(4-chlorophenyl)ethyl)-1H-tetrazol-5- (M + Na)⁺yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine. 175 684.41-(1-((R)-1-(4-methoxyphenyl)ethyl)-1H-tetrazol-5- (M + Na)⁺yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine. 176 654.41-(1-(4-fluorobenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan- 1-amine. 177 654.41-(1-(2-fluorobenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan- 1-amine. 178 670.31-(1-(3-chlorobenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan- 1-amine. 179 670.31-(1-(2-chlorobenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan- 1-amine. 180 714.31-(1-(4-bromobenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5- [M(Br⁷⁹) +tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan- Na]⁺; 1-amine.716.3 [M(Br⁸¹) + Na]⁺ 181 661.44-((5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- (M + Na)⁺2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1- yl)methyl)benzonitrile 182704.4 1-(1-(2,4-dichlorobenzyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine.183 704.4 1-(1-(3,4-dichlorobenzyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine.184 732.3 1-(1-(4-bromo-2-fluorobenzyl)-1H-tetrazol-5-yl)- [M(Br⁷⁹) +5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- Na]⁺;N-tritylpentan-1-amine 734.3 [M(Br⁸¹) + Na]⁺. 185 666.41-(1-(2-methoxybenzyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine.186 656.4 3-phenyl-3-(5-(5-(4,4,5,5-tetramethyl-1,3,2- (M − H)⁺dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H- tetrazol-1-yl)propan-1-ol.187 637.4 1-(1-(pyridin-3-ylmethyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N- tritylpentan-1-amine.188 642.3 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- (M + Na)⁺1-(1-(thiophen-2-ylmethyl)-1H-tetrazol-5-yl)- N-tritylpentan-1-amine.190 668.4 1-(1-(4-fluorophenethyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- N-tritylpentan-1-amine.191 710.4 1-(1-(3,4-dimethoxyphenethyl)-1H-tetrazol-5- (M + Na)⁺yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine. 192 680.41-(1-(2-methoxyphenethyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- N-tritylpentan-1-amine.193 642.3 4-(2-(5-(5-(4,4,5,5-tetramethyl-1,3,2- (M − H)⁺dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)ethyl)phenol. 194 680.41-(1-(3-methoxyphenethyl)-1H-tetrazol-5-yl)- (M + Na)⁺5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-N-tritylpentan-1-amine.195 664.5 1-(1-(3-phenylpropyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- N-tritylpentan-1-amine.196 728.3 1-(1-(4-bromophenethyl)-1H-tetrazol-5-yl)-5- [M(Br⁷⁹) +(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- Na]⁺;N-tritylpentan-1-amine. 730.3 [M(Br⁸¹) + Na]⁺. 197 672.41-(1-(2,5-difluorobenzyl)-1H-tetrazol-5-yl)-5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- N-tritylpentan-1-amine.198 705.3 N-(2,4-difluorobenzyl)-2-(5-(5-(4,4,5,5- (M − H)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 199 683.5N-(4-methylbenzyl)-2-(5-(5-(4,4,5,5-tetramethyl- (M − H)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 200 741.5N-(4-chlorophenethyl)-2-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 201 721.3N-(4-chloro-2-fluorobenzyl)-2-(5-(5-(4,4,5,5- (M − H)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 202 705.5N-(2,6-difluorobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl- (M − H)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 203 694.4N-(4-cyanobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl- (M − H)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 204 745.4N-(4-chlorobenzyl)-3-methyl-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)butanamide 205 747.4N-(4-bromobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl- (M(Br⁷⁹) −1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)- H]⁺;1H-tetrazol-1-yl)acetamide. 749.4 [M(Br⁸¹) − H]⁺ 206 672.36-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- (M + Na)⁺1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)-N-tritylhexan-1-amine. 207 707.4N-benzyl-2-(5-(6-(4,4,5,5-tetramethyl-1,3,2- (M + Na)⁺dioxaborolan-2-yl)-1-(tritylamino)hexyl)-1H- tetrazol-1-yl)acetamide.208 741.3 N-(4-chlorobenzyl)-2-(5-(6-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)hexyl)-1H-tetrazol-1-yl)acetamide. 209 655.4N-(prop-2-yn-1-yl)-2-(5-(6-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)hexyl)-1H-tetrazol-1-yl)acetamide. 210 721.5N-phenethyl-2-(5-(6-(4,4,5,5-tetramethyl-1,3,2- (M + Na)⁺dioxaborolan-2-yl)-1-(tritylamino)hexyl)-1H- tetrazol-1-yl)acetamide.211 783.2 N-((perfluorophenyl)methyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 212 765.2N-(2,3,4,5-tetrafluorobenzyl)-2-(5-(5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 213 747.22-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- (M + Na)⁺2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)-N-(2,4,6-trifluorobenzyl)acetamide. 214 728.2N-((6-chloropyridin-3-yl)methyl)-2-(5-(5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 215 729.2N-(2,3-difluorobenzyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 216 729.2N-(2,5-difluorobenzyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 217 729.2N-(3,5-difluorobenzyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 218 747.22-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- (M + Na)⁺2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)-N-(2,3,4-trifluorobenzyl)acetamide 219 747.22-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- (M + Na)⁺2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)-N-(2,3,5-trifluorobenzyl)acetamide. 220 747.22-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- (M + Na)⁺2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)-N-(3,4,5-trifluorobenzyl)acetamide. 221 747.22-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- (M + Na)⁺2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)-N-(2,3,6-trifluorobenzyl)acetamide. 222 765.2N-(2,3,5,6-tetrafluorobenzyl)-2-(5-(5-(4,4,5,5 (M + Na)⁺-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 223 729.2N-(3,4-difluorobenzyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 224 747.22-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- (M + Na)⁺2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)-N-(2,4,5-trifluorobenzyl)acetamide. 225 767.41-(1-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)- (M + Na)⁺1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine. 226 707.3N-((R)-1-phenylethyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 227 728.14-chloro-N-(2-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)ethyl)benzamide. 228 554.3N-(4-chlorobenzyl)-2-(5-(1-((pyridin-4- (M + H)⁺ylmethyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl)-1H-tetrazol-1- yl)acetamide. 229 560.4tert-butyl ((1-(1-(1-(2-((4-chlorobenzyl)amino)- (M + H)⁺2-oxoethyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl)piperidin-4-yl)methyl)carbamate. 230 560.3N-(4-chlorobenzyl)-2-(5-(1-((1-methylpiperidin- (M + H)⁺4-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl)-1H-tetrazol-1- yl)acetamide.

Example 231:N-(2-fluorobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide

Under the N₂ atmosphere methyl2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetate(0.5 g, 0.839 mmol, obtained in example 131) and (2-fluorophenyl)methanamine (0.48 mL, 4.19 mmol) mixed together and stirred at roomtemperature for 16 h. Excess amine was removed by washing with petroleumether and decantation procedure (3 ×20 mL). The crude residue waspurified using flash chromatography to provideN-(2-fluorobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide(0.4 g).

¹H NMR (500 MHz, Chloroform-d) δ7.36-7.30 (m, 6H), 7.25-7.21 (m, 1H),7.21-7.15 (m, 7H), 7.15-7.10 (m, 3H), 7.08 (td, J=7.5, 1.2 Hz, 1H), 7.02(ddd, J=9.5, 8.1, 1.2 Hz, 1H), 6.26 (t, J=5.9 Hz, 1H), 4.80 (d, J=16.7Hz, 1H), 4.53-4.30 (m, 3H), 4.01 (q, J=7.6 Hz, 1H), 2.93 (d, J=7.4 Hz,1H), 1.91-1.80 (m, 1H), 1.80-1.69 (m, 1H), 1.31-1.23 (m, 2H), 1.20 (s,12H), 1.15-0.94 (m, 2H), 0.64 (td, J=7.6, 2.3 Hz, 2H); LC-MS (EI) m/z:711.4 (M+Na)⁺.

Example 232 to 233 were prepared in Analogues Manner of Example 231 fromthe Appropriate Intermediate that are Commercially or Synthesized asAbove

Ex. LC-MS No. (EI)m/z: IUPAC Name 232 727.5N-(4-chlorobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl- (M + Na)⁺1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 233 707.4N-phenethyl-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2- (M + Na)⁺dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H- tetrazol-1-yl)acetamide.

Example 234:2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetic acid

To a stirred solution of methyl2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetate(3.5 g, 5.87 mmol, obtained in example 131) in THF (12.0 mL) was addedLiOH (0.423 g, 17.63 mmol) dissolved in H₂O (6.0 mL) and MeOH (1.0 mL)and the reaction mixture was stirred for 16 h. The solvent was removedunder reduced pressure and the residue was re-dissolved in H₂O (10 mL),cooled to 0° C. and acidified with 1N aqueous HCl to pH˜4-5 andextracted with ethyl acetate (3×100 mL). Combined organic layer waswashed with brine (100 mL), dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure to obtain2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)aceticacid as a white solid (2.45 g) LC-MS (EI) m/z: 604.3 (M+Na)⁺.

Example 235:N-(4-chlorophenyl)-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide:

To a stirred solution of2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)aceticacid (0.15 g, 0.258 mmol) in DMF (2.0 mL) was added 4-chloroaniline(0.050 g, 0.38 mmol), HOBt.HCl (0.035 g, 0.258 mmol) and NMM (0.1 mL,0.774 mmol). After 0.5 h of stirring, EDCI.HCl (0.098 g, 0.516 mmol) wasadded and the reaction mixture was further stirred at room temperatureof 16 h. The reaction mixture was poured on ice-cold water, solidprecipitated out, collected by filtration and vacuum dried to obtaintitle compound as a pale yellow solid (0.210 g).

¹H NMR (500 MHz, Chloroform-d) δ7.88 (s, 1H), 7.41-7.31 (m, 8H),7.31-7.25 (m, 2H), 7.19 (t, J=7.7 Hz, 6H), 7.17-7.08 (m, 3H), 4.88 (d,J=16.6 Hz, 1H), 4.55 (d, J=16.6 Hz, 1H), 4.11-4.03 (m, 1H), 2.99 (d,J=7.2 Hz, 1H), 1.93-1.78 (m, 2H), 1.35-1.26 (m, 2H), 1.19 (s, 12H), 1.16-1.05 (m, 1H), 1.05-0.92 (m, 1H), 0.60 (td, J=7.8, 7.1, 2.3 Hz, 2H); ¹³CNMR (126 MHz, Chloroform-d) δ162.21, 158.75, 144.94, 135.41, 130.25,129.18, 128.58, 128.05, 126.90, 121.52, 83.02, 71.65, 50.54, 48.91,37.13, 27.67, 24.87, 23.84, 10.94; LC-MS (EI) m/z: 713.2 (M+Na)⁺.

Example 236 and 237 were Prepared in Analogues Manner of Example 235from the Appropriate Intermediate that are Commercially or Synthesizedas Above

Ex. LC-MS No. (EI)m/z: IUPAC Name 236 760.3N-((6-(1H-imidazol-1-yl)pyridin-3-yl)methyl)-2-(5-(5- (M + Na)⁺(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide. 237 769.3N-([1,1′-biphenyl]-4-ylmethyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide.

Example 238:N-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide

To a stirred solution ofN-(prop-2-yn-1-yl)-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide(0.1 g, 0.161 mmol, obtained in example 157) in DMF (1.0 mL) was addedaqueous solution of Cu(II)SO₄.5H₂O (0.025 g in 0.4 mL H₂O, 0.097 mmol)and ascorbic acid (0.092 g in 0.4 mL H₂O, 0.466 mmol) respectivelyfollowed by 1-(azidomethyl)-4-chlorobenzene (0.035 g, 0.209 mmol) andfurther stirred for 14 h. The reaction mixture was poured on ice-coldwater, solid precipitated out, collected by filtration and vacuum driedand further purified by flash chromatography to obtain title compound asa pale yellow solid (0.110 g).

¹H NMR (500 MHz, Chloroform-d) δ8.01 (s, 1H), 7.36-7.29 (m, 9H),7.20-7.15 (m, 11H), 5.43-5.32 (m, 2H), 4.80 (d, J=16.5 Hz, 1H), 4.42(dt, J=5.9, 3.0 Hz, 3H), 4.38-4.31 (m, 2H), 4.07-3.93 (m, 1H), 1.90-1.80(m, 1H), 1.74-1.66 (m, 1H), 1.27 (ddd, J=13.3, 9.3, 6.7 Hz, 2H), 1.20(d, J=4.3 Hz, 12H), 1.14-0.98 (m, 2H), 0.63 (tt, J=8.4, 4.1 Hz, 2H);LC-MS (EI) m/z: 785.08 (M−H)⁺.

Example 239:N-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamideExample 239 was Prepared in Analogues Manner of Example 238, startingfrom Appropriate Intermediates that are Available Commercially orSynthesized as Above

Ex. LC-MS No. (EI)m/z: IUPAC Name 239 730.3N-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)- (M + Na)⁺2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide.

Examples 240-247: Chirally Pure Compounds Analytical Methods used forChiral Separation

Method-1:—Column-Chiral IC (250×4.6) mm, 5 mm; Flow: 4.0 ml min⁻¹;Mobile Phase: Isocratic; Ethanol: CO₂ (13:87); Column Temperature: 40°C., Detection wavelength: photodiode array (PDA); Pressure: 120 bar; Runlength: 18 min.

Method-2: Column-Chiral IC (250×4.6) mm, 5 mm; Flow: 4.0 ml min⁻¹;Mobile Phase: Isocratic; Ethanol: CO₂ (20:80); Column Temperature: 40°C., Detection wavelength: photodiode array (PDA); Pressure: 120 bar; Runlength: 15 min.

Method-3:—Column-Chiral IC (250×4.6) mm, 5 mm; Flow: 4.0 ml min ⁻¹;Mobile Phase: Isocratic; Ethanol: CO₂ (14:86); Column Temperature: 40°C., Detection wavelength: photodiode array (PDA); Pressure: 120 bar; Runlength: 25 min.

Method-4:—Column-Chiral IC (250×4.6) mm, 5 mm; Flow: 4.0 ml min⁻¹;Mobile Phase: Isocratic; Ethanol: CO₂ (15:85); Column Temperature: 40°C., Detection wavelength: photodiode array (PDA); Pressure: 120 bar; Runlength: 30 min.

Ex. LC-MS Method No. (EI)m/z: IUPAC Name and Chiral HPLC RT Used 240641.4 (−)-N-(prop-2-yn-1-yl)-2-(5-(5-(4,4,5,5- Method (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1- 1(tritylamino)pentyl)-1H-tetrazol-1- yl)acetamide. Peak1-RT = 10.6 min241 641.4 (+)-N-(prop-2-yn-1-yl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1- yl)acetamide. Peak2-RT = 13 min 242727.5 (−)-(R)-N-(4-chlorobenzyl)-2-(5-(5-(4,4,5,5- Method (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1- 2(tritylamino)pentyl)-1H-tetrazol-1- yl)acetamide. Peak1-RT = 6.5 min 243727.5 (+)-(S)-N-(4-chlorobenzyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1- yl)acetamide. Peak2-RT = 9.4 min 244711.4 (−)-N-(2-fluorobenzyl)-2-(5-(5-(4,4,5,5- Method (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1- 3(tritylamino)pentyl)-1H-tetrazol-1- yl)acetamide. Peak1-RT = 15.1 min245 711.4 (+)-N-(2-fluorobenzyl)-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1- yl)acetamide. Peak2-RT = 22.1 min246 707.4 (−)-N-phenethyl-2-(5-(5-(4,4,5,5- Method (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1- 4(tritylamino)pentyl)-1H-tetrazol-1- yl)acetamide. Peak1-RT = 22.1 min247 707.4 (+)-N-phenethyl-2-(5-(5-(4,4,5,5- (M + Na)⁺tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1- yl)acetamide. Peak2-RT = 22.1 min

Example 248:(5-amino-5-(1-(4-chlorobenzyl)-1H-tetrazol-5-yl)pentyl)boronic acidhydrochloride

1-(1-(4-chlorobenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine(0.2 g, 0.308 mmol, obtained in example 129) was dissolved in DCM (1.0mL) to it was added 3N aqueous HCl (5.0 mL) and resulted reactionmixture was heated at 70° C. for 18 h. The reaction mixture was furtherdiluted with 5.0 mL water and the aqueous layer was washed with DCM(2×10 mL). The aqueous phase was concentrated to dryness under reducedpressure afforded the title off white solid (0.095 g).

¹H NMR (500 MHz, Methanol-d₄) δ7.43 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.5Hz, 2H), 5.85 (d, J=15.7 Hz, 1H), 5.70 (d, J=15.7 Hz, 1H), 3.64-3.53 (m,1H), 1.94-1.74 (m, 2H), 1.27-1.08 (m, 2H), 1.08-0.88 (m, 2H), 0.60 (t,J=7.7 Hz, 2H); LC-MS (EI) m/z: 338.1 (M+15)⁺.

Example 249:(5-amino-5-(1-(2-fluoro-5-nitrophenyl)-1H-tetrazol-5-yl)pentyl)boronicacid hydrochloride

The compound of example 249 was obtained by similar method described inexample 248 using1-(1-(2-fluoro-5-nitrophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-tritylpentan-1-amine(0.1 g, 0.15 mmol, obtained in example 130) in DCM (0.5 mL), 3N aqueousHCl (3.0 mL) heated at 70° C. for 18 h to provide the title compound(0.050 g)

¹H NMR (500 MHz, Methanol-d₄) δ8.64 (dt, J=9.0, 2.6 Hz, 1H), 8.61 (t,J=2.5 Hz, 1H), 7.86 (dd, J=8.9, 2.3 Hz, 1H), 4.79-4.71 (m, 1H),2.07-1.88 (m, 2H), 1.38-1.08 (m, 4H), 0.78-0.59 (m, 2H); LC-MS (EI) m/z:339.1 (M+H)⁺.

Example 250:2-(5-(1-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl)-1H-tetrazol-1-yl)aceticacid hydrochloride

The compound of example 250 was obtained by similar method described inexample 248 using Methyl 2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetate(0.2 g, 0.335 mmol, obtained in example 131) in DCM (0.5 mL), 3N aqueousHCl (5.0 mL) heated at 100° C. for 18 h to provide the title compound(0.090 g) NMR; LC-MS (EI) m/z: 256.2 (M−H)⁺.

Example 251: (5-amino-5-(1H-tetrazol-5-yl)hexyl)boronic acidhydrochloride:

The compound of example 251 was obtained by similar method described inexample 248 using N-(4-methoxybenzyl)-6-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)hexan-2-amine(0.1 g, 0.335 mmol, obtained in example 136) in DCM (0.5 mL), 3N aqueousHCl (3.0 mL) heated at 100° C. for 18 h to provide the title compound(0.040 g)

¹H NMR (500 MHz, Methanol-d₄) δ2.15-2.00 (m, 2H), 1.80 (s, 3H),1.42-1.31 (m, 2H), 1.30 -1.14 (m, 3H), 0.81-0.69 (m, 2H); LC-MS (EI)m/z: 228.2 (M+15)⁺.

Example 252: (6-amino-6-(1H-tetrazol-5-yl)hexyl)boronic acidhydrochloride

The compound of example 252 was obtained by similar method described inexample 248 using6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)-N-tritylhexan-1-amine(0.15 g, 0.230 mmol, obtained in example 138) in DCM (0.5 mL), 3Naqueous HCl (4.0 mL) heated at 70° C. for 18 h to provide the titlecompound (0.050 g)

NMR; LC-MS (EI) m/z: 214.2 (M+H)⁺.

Example 253:(5-amino-5-(1-(2-((2-fluorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronicacid hydrochloride

The compound of example 253 was obtained by similar method described inexample 248 usingN-(2-fluorobenzyl)-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tritylamino)pentyl)-1H-tetrazol-1-yl)acetamide(0.15 g, 0.217 mmol, obtained in example 231) in DCM (0.5 mL), 3Naqueous HCl (4.0 mL) heated at 70° C. for 18 h to provide the titlecompound (0.080 g)

(Major rotamer is given) ¹H NMR (500 MHz, Deuterium Oxide) δ7.43-7.35(m, 2H), 7.21-7.11 (m, 2H), 5.45 (q, J=35.5, 17.7 Hz, 2H), 4.89 (t,J=7.1 Hz, 1H), 4.17 (s, 2H), 2.16-1.99 (m, 2H), 1.37-1.09 (m, 4H), 0.64(t, J=7.8 Hz, 2H); LC-MS (EI) m/z: 379.2 (M+15)⁺.

Example 254 to 362 were Prepared in Analogues Manner of Example 248-253from the Appropriate Intermediate that are Available Commercially orSynthesized as Above

Ex. LC-MS No (EI) m/z: IUPAC Name 254 304.2(5-amino-5-(1-benzyl-1H-tetrazol-5- (M + 15)⁺ yl)pentyl)boronic acidhydrochloride. 255 228.1 (5-(methylamino)-5-(1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 256 322.2(5-amino-5-(1-(3-fluorobenzyl)-1H-tetrazol-5- (M + 15) yl)pentyl)boronic acid hydrochloride. 257 318.2(5-amino-5-(1-phenethyl-1H-tetrazol-5- (M + 15)⁺ yl)pentyl)boronic acidhydrochloride. 258 296.2 (5-amino-5-(1-cyclohexyl-1H-tetrazol-5- (M +15)⁺ yl)pentyl)boronic acid hydrochloride. 259 214.2(5-amino-5-(1H-tetrazol-5-yl)pentyl)boronic acid (M + 15)⁺hydrochloride. 260 347.2 (5-amino-5-(1-(2-(benzylamino)-2-oxoethyl)-1H-(M + H)⁺ tetrazol-5-yl)pentyl)boronic acid hydrochloride. 261 409.2(5-(1-(2-fluoro-5-nitrophenyl)-1H-tetrazol-5-yl)- (M + H)⁺5-morpholinopentyl)boronicacid hydrochloride. 262 406.2(5-amino-5-(1-(2-morpholino-5-nitrophenyl)-1H- (M + H)⁺tetrazol-5-yl)pentyl)boronicacid hydrochloride 262 228.2(5-amino-5-(1H-tetrazol-5-yl)hexyl)boronicacid (M + 15)⁺ hydrochloride.263 381.1 (5-amino-5-(1-(2-((4-chlorobenzyl)amino)-2- (M + H)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 264 361.2(5-amino-5-(1-(2-oxo-2-(((S)-1- (M + H)⁺phenylethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 265 353.2 (5-amino-5-(1-(2-oxo-2-((thiophen-2- (M + H)⁺ylmethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 266 361.2 5-Amino-5-(1-(2-oxo-2-(phenethylamino)ethyl)-(M + H)⁺ 1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 267 430.3(5-amino-5-(1-(2-((1-benzylpiperidin-4- (M + H)⁺yl)amino)-2-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 268 297.2 (5-amino-5-(1-(2-(cyclopropylamino)-2- (M + H)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 269 370.4(5-amino-5-(1-(2-((2-morpholinoethyl)amino)-2- (M + H)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 270 421.2(5-amino-5-(1-(2-((3,4- (M + H)⁺dimethoxyphenethyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronicacid hydrochloride. 271 297.1(5-amino-5-(1-(2-(butylamino)-2-oxoethyl)-1H- (M + H)⁺tetrazol-5-yl)pentyl)boronic acid hydrochloride. 272 295.1(5-amino-5-(1-(2-oxo-2-(prop-2-yn-1- (M + H)⁺ylamino)ethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 273416.2 (5-amino-5-(1-(2-(4-benzylpiperazin-1-yl)-2- (M + H)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 274 416.2(5-amino-5-(1-(2-morpholino-2-oxoethyl)-1H- (M + H)⁺tetrazol-5-yl)pentyl)boronic acid hydrochloride. 275 311.2(5-amino-5-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)- (M + H)⁺1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 276 381.2(5-amino-5-(1-(2-((3-chlorobenzyl)amino)-2- (M + H)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 277 381.2(5-amino-5-(1-(2-((2-chlorobenzyl)amino)-2- (M + H)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 278 348.2(5-amino-5-(1-(2-oxo-2-((pyridin-3- (M + H)⁺ylmethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 279 377.2 (5-amino-5-(1-(2-((4-methoxybenzyl)amino)-2-(M + H)⁺ oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride.280 348.2 (5-amino-5-(1-(2-oxo-2-((pyridin-4- (M + H)⁺ylmethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 281 395.2 (5-amino-5-(1-(3-((4-chlorobenzyl)amino)-3-(M + H)⁺ oxopropyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride.282 375.2 (5-amino-5-(1-(3-oxo-3-(phenethylamino)propyl)- (M + H)⁺1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 283 284.14-(5-(1-amino-5-boronopentyl)-1H-tetrazol-1- (M − H)⁺ yl)butanoic acidhydrochloride. 284 243.2(5-(1-(2-(1H-indol-3-yl)ethyl)-1H-tetrazol-5-yl)- (M + H)⁺5-aminopentyl)boronic acid hydrochloride. 285 405.3(5-amino-5-(1-(2-(benzyl(2-hydroxyethyl)amino)- (M + 15)⁺2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 286361.2 (5-amino-5-(1-(2-(benzyl(methyl)amino)-2- (M + H)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 287 395.3(5-amino-5-(1-(2-(((S)-1-(4- (M + H)⁺chlorophenyl)ethyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronicacid hydrochloride. 288 318.2(5-amino-5-(1-(1-phenylethyl)-1H-tetrazol-5- (M + 15)⁺ yl)pentyl)boronicacid hydrochloride. 289 318.2(5-amino-5-(1-((S)-1-phenylethyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 290 318.2(5-amino-5-(1-((R)-1-phenylethyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 291 352.2(5-amino-5-(1-((S)-1-(4-chlorophenyl)ethyl)-1H- (M + 15)⁺tetrazol-5-yl)pentyl)boronic acid hydrochloride. 292 352.2(5-amino-5-(1-((R)-1-(4-chlorophenyl)ethyl)-1H- (M + 15)⁺tetrazol-5-yl)pentyl)boronic acid hydrochloride. 293 348.2(5-amino-5-(1-((R)-1-(4-methoxyphenyl)ethyl)- (M + 15)⁺1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 294 322.1(5-amino-5-(1-(4-fluorobenzyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 295 322.1(5-amino-5-(1-(2-fluorobenzyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 296 338.2(5-amino-5-(1-(3-chlorobenzyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 297 338.2(5-amino-5-(1-(2-chlorobenzyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 298 381.1(5-amino-5-(1-(4-bromobenzyl)-1H-tetrazol-5- [M (Br⁷⁹) +yl)pentyl)boronic acid hydrochloride. 15]⁺; 383.1 [M (Br⁸¹) + 15]⁺ 299329.2 (5-amino-5-(1-(4-cyanobenzyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 300 372.0(5-amino-5-(1-(2,4-dichlorobenzyl)-1H-tetrazol- (M + 15)⁺5-yl)pentyl)boronic acid hydrochloride. 301 372.0(5-amino-5-(1-(3,4-dichlorobenzyl)-1H-tetrazol- (M + 15)⁺5-yl)pentyl)boronic acid hydrochloride. 302 399.1(5-amino-5-(1-(4-bromo-2-fluorobenzyl)-1H- [M (Br⁷⁹) +tetrazol-5-yl)pentyl)boronic acid hydrochloride. 15]⁺; 401.1 [M (Br⁸¹) +15]⁺ 303 334.2 (5-amino-5-(1-(2-methoxybenzyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 304 334.2(5-amino-5-(1-(3-hydroxy-1-phenylpropyl)-1H- (M + H)⁺tetrazol-5-yl)pentyl)boronic acid hydrochloride. 305 305.2(5-amino-5-(1-(pyridin-3-ylmethyl)-1H-tetrazol- (M + 15)⁺5-yl)pentyl)boronic acid hydrochloride. 306 310.1(5-amino-5-(1-(thiophen-2-ylmethyl)-1H-tetrazol- (M + 15)⁺5-yl)pentyl)boronic acid hydrochloride. 307 336.2(5-amino-5-(1-(4-fluorophenethyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 308 378.2(5-amino-5-(1-(3,4-dimethoxyphenethyl)-1H- (M + 15)⁺tetrazol-5-yl)pentyl)boronic acid hydrochloride. 309 348.2(5-amino-5-(1-(2-methoxyphenethyl)-1H-tetrazol- (M + 15)⁺5-yl)pentyl)boronic acid hydrochloride. 310 318.3(5-amino-5-(1-(4-hydroxyphenethyl)-1H-tetrazol- (M − H)⁺5-yl)pentyl)boronic acid hydrochloride. 311 348.2(5-amino-5-(1-(3-methoxyphenethyl)-1H-tetrazol- (M + 15)⁺5-yl)pentyl)boronic acid hydrochloride. 312 332.2(5-amino-5-(1-(3-phenylpropyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 313 431.1(5-amino-5-(1-(4-bromophenethyl)-1H-tetrazol-5- [M (Br⁷⁹) +yl)pentyl)boronic acid hydrochloride. 15]⁺; 433.1 [M (Br⁸¹) + 15]⁺ 314340.2 (5-amino-5-(1-(2,5-difluorobenzyl)-1H-tetrazol-5- (M + 15)⁺yl)pentyl)boronic acid hydrochloride. 315 383.1(5-amino-5-(1-(2-((2,4-difluorobenzyl)amino)-2- (M + H)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 316 361.2(5-amino-5-(1-(2-((4-methylbenzyl)amino)-2- (M + 15)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 317 395.2(5-amino-5-(1-(2-((4-chlorophenethyl)amino)-2- (M + 15)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 318 435.3(5-amino-5-(1-(2-((4-chloro-2- (M + 15)⁺fluorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 319 383.1 (5-amino-5-(1-(2-((2,6-difluorobenzyl)amino)-2-(M + 15)⁺ oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride.320 386.2 (5-amino-5-(1-(2-((4-cyanobenzyl)amino)-2- (M + 15)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 321 437.2(5-amino-5-(1-(1-((4-chlorobenzyl)amino)-3- (M + 15)⁺methyl-1-oxobutan-2-yl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 322 451.3 (5-amino-5-(1-(1-((4-chlorobenzyl)amino)-4-(M + 15)⁺ methyl-1-oxopentan-2-yl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride 323 424.1 (5-amino-5-(1-(2-((4-bromobenzyl)amino)-2- [M(Br⁷⁹) + oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid H]⁺;hydrochloride. 426.1 [M (Br⁸¹) + H]⁺ 324 375.2(6-amino-6-(1-(2-(benzylamino)-2-oxoethyl)-1H- (M + 15)⁺tetrazol-5-yl)hexyl)boronic acid hydrochloride. 325 409.2(6-amino-6-(1-(2-((4-chlorobenzyl)amino)-2- (M + 15)⁺oxoethyl)-1H-tetrazol-5-yl)hexyl)boronic acid hydrochloride. 326 443.2(6-amino-6-(1-(2-((2,4-dichlorobenzyl)amino)-2- (M + 15)⁺oxoethyl)-1H-tetrazol-5-yl)hexyl)boronic acid hydrochloride. 327 323.2(6-amino-6-(1-(2-oxo-2-(prop-2-yn-1- (M + 15)⁺ylamino)ethyl)-1H-tetrazol-5-yl)hexyl)boronic acid hydrochloride. 328389.3 (6-amino-6-(1-(2-oxo-2-(phenethylamino)ethyl)- (M + 15)⁺1H-tetrazol-5-yl)hexyl)boronic acid hydrochloride. 329 451.1(5-amino-5-(1-(2-oxo-2- (M + 15)⁺(((perfluorophenyl)methyl)amino)ethyl)-1H- tetrazol-5-yl)pentyl)boronicacid hydrochloride. 330 433.1 (5-amino-5-(1-(2-oxo-2-((2,3,4,5- (M +15)⁺ tetrafluorobenzyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronicacid hydrochloride. 331 415.2 (5-amino-5-(1-(2-oxo-2-((2,4,6- (M + 15)⁺trifluorobenzyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 332 396.3 (5-amino-5-(1-(2-(((6-chloropyridin-3- (M +15)⁺ yl)methyl)amino)-2-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 333 379.2 (5-amino-5-(1-(2-((3-fluorobenzyl)amino)-2-(M + 15)⁺ oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride.334 383.1 (5-amino-5-(1-(2-((2,3-difluorobenzyl)amino)-2- (M + 15)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 335 383.1(5-amino-5-(1-(2-((2,5-difluorobenzyl)amino)-2- (M + 15)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 336 383.1(5-amino-5-(1-(2-((3,5-difluorobenzyl)amino)-2- (M + 15)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 337 415.2(5-amino-5-(1-(2-oxo-2-((2,3,4- (M + 15)⁺trifluorobenzyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 338 415.2 (5-amino-5-(1-(2-oxo-2-((2,3,5- (M + 15)⁺trifluorobenzyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 339 415.2 (5-amino-5-(1-(2-oxo-2-((3,4,5- (M + 15)⁺trifluorobenzyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride 340 415.2 (5-amin o-5-(1-(2-oxo-2-((2,3,6- (M + 15)⁺trifluorobenzyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 341 433.1 (5-amino-5-(1-(2-oxo-2-((2,3,5,6- (M + 15)⁺tetrafluorobenzyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 342 383.1 (5-amino-5-(1-(2-((3,4-difluorobenzyl)amino)-2-(M + 15)⁺ oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride.343 415.2 (5-amino-5-(1-(2-oxo-2-((2,4,5- (M + 15)⁺trifluorobenzyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 344 435.8 (5-amino-5-(1-((1-(4-chlorobenzyl)piperidin-4-(M + 15)⁺ yl)methyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride.345 375.2 (5-amino-5-(1-(2-oxo-2-(((R)-1- (M + 15)⁺phenylethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 346 398.2 (5-amino-5-(1-(2-(((1-(2-fluoroethyl)-1H-1,2,3-(M + 15)⁺ triazol-4-yl)methyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 347 395.2(5-amino-5-(1-(2-(4-chlorobenzamido)ethyl)-1H- (M + 15)⁺tetrazol-5-yl)pentyl)boronic acid hydrochloride 348 476.2(5-amino-5-(1-(2-(((1-(4-chlorobenzyl)-1H-1,2,3- (M + 15)⁺triazol-4-yl)methyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronicacid hydrochloride 349 486.2(5-(1-(2-((4-chlorobenzyl)amino)-2-oxoethyl)- (M + 15)⁺1H-tetrazol-5-yl)-5-((pyridin-4- ylmethyl)amino)pentyl)boronic acidhydrochloride. 350 492.3 (5-(4-(aminomethyl)piperidin-1-yl)-5-(1-(2-((4-(M + 15)⁺ chlorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 351 492.2(5-(1-(2-((4-chlorobenzyl)amino)-2-oxoethyl)- (M + 15)⁺1H-tetrazol-5-yl)-5-((1-methylpiperidin-4- yl)amino)pentyl)boronic acidhydrochloride. 352 437.2 (5-(1-(2-(([1,1′-biphenyl]-4-ylmethyl)amino)-2-(M + 15)⁺ oxoethyl)-1H-tetrazol-5-yl)-5- aminopentyl)boronic acid 353428.2 (5-(1-(2-(((6-(1H-imidazol-1-yl)pyridin-3- (M + 15)⁺yl)methyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)- 5-aminopentyl)boronicacid hydrochloride. 354 381.3(5-amino-5-(1-(2-((4-chlorophenyl)amino)-2- (M + 15)⁺oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 355 295.1(+)-(R)-(5-amino-5-(1-(2-oxo-2-(prop-2-yn-1- (M + H)⁺ylamino)ethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 356295.1 (−)-(S)-(5-amino-5-(1-(2-oxo-2-(prop-2-yn-1- (M + H)⁺ylamino)ethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 357381.1 (+)-(R)-(5-amino-5-(1-(2-((4- (M + H)⁺chlorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 358 365.2 (−)-(S)-(5-amino-5-(1-(2-((4- (M + H)⁺chlorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 359 365.2 (+)-(R)-(5-amino-5-(1-(2-((2- (M + H)⁺fluorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 360 365.2 (−)-(S)-(5-amino-5-(1-(2-((2- (M + H)⁺fluorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 361 361.2 (+)-(R)-(5-amino-5-(1-(2-oxo-2- (M + H)⁺(phenethylamino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 362 361.2 (−)-(S)-(5-amino-5-(1-(2-oxo-2- (M + H)⁺(phenethylamino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 363 365.2 (5-amino-5-(1-(2-((4-fluorobenzyl)amino)-2-(M + H)⁺ oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride.

Example 364:(5-amino-5-(1-(5-amino-2-fluorophenyl)-1H-tetrazol-5-yl)pentyl)boronicacid hydrochloride

Under the nitrogen atmosphere to the stirred solution of(5-amino-5-(1-(2-fluoro-5-nitrophenyl)-1H-tetrazol-5-yl)pentyl)boronicacid hydrochloride (0.080 g, obtained in example 249) in methanol (3.0mL) was added 10% Pd/C (0.030 g) and hydrogenation reaction was carriedout using hydrogen balloon for 2.5 h. Reaction mixture was filteredthrough the celite pad. The Celite pad was washed with excess methanol.Finally solvent was removed under reduced pressure to obtain the titlecompound (0.035 g).

¹ HNMR (500 MHz, Methanol-d₄) δ6.89 (t, J=2.4 Hz, 2H), 6.62 (s, 1H),4.54-4.42 (m, 1H), 2.05-1.78 (m, 2H), 1.36-1.16 (m, 4H), 0.68 (t, J=6.9Hz, 2H); LC-MS (EI) m/z: 323.2 (M+15)⁺.

Examples 365 and 366 were prepared in Analogues Manner of Example 355from the Appropriate Intermediate that are Available Commercially orSynthesized as Above

Ex. LC-MS No (EI)m/z: IUPAC Name 365 376.25-amino-5-(1-(5-amino-2-morpholinophenyl)-1H- (M + 15)⁺tetrazol-5-yl)pentyl)boronic acid hydrochloride. 366 438.2(5-amino-5-(1-(5-amino-2-(1,1- (M + 15)⁺dioxidothiomorpholino)phenyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride.

Inhibition of Arginase

The compounds of the present invention inhibit human arginase I (ARG I)and arginase II (ARG II) as evidenced by an ex vivo assay set forth by apublished protocol (Baggio et al. J. Pharmacol. Exp. Ther. 1999, 290,1409-1416). The assay established the concentration of inhibitor that isrequired to reduce arginase activity by 50% (IC₅₀).

Assay Protocol

Inhibition of arginase I (ARG I) and arginase II (ARGG II) novelcompounds is followed spectrophotometrically at 530 nm. The compound tobe tested is dissolved in H₂O and prepared 100 mM stock solution. 10 μlof the stock solution is diluted in 90 μl of the assay buffer thatcomprises 0.1M sodium phosphate buffer containing 130 mM NaCl, pH 7.4,to which is added ovalbumin (OVA) at a concentration of 1 mg/mi.Solutions of arginase I and II are prepared in 100 mM sodium phosphatebuffer, pH 7.4 containing 1 mg/ml OVA to give an arginase stock solutionat a final concentration of 100 ng/ml. To each well of a 96-wellmicrotiter plate is add 40 μ1 of enzyme, 10 μl of an inventive compoundand 10 μl of enzyme substrate (L-arginine+manganese sulfate). For wellsthat are used as positive controls, only the enzyme and its substrateare added, while wells used as negative controls contain only manganesesulfate. After incubating the microtiter plate at 37° C. for 60 minutes,150 μl of a urea reagent obtained by combining equal proportions (1:1)of reagents A and B is added to each well of the microtiter plate tostop the reaction. The urea reagent is made just before use by combiningReagent A (10 mM o-phthaldialdehyde, and 0.4% polyoxyethylene (23)lauryl ether (w/v) in 1.8 M sulfuric acid) with Reagent B (1.3 mMprimaquinone diphosphate, 0.4% polyoxyethylene (23) lauryl ether (w/v),130 mM boric acid in 3.6 M sulfuric acid). After quenching the reactionmixture, the microtiter plate is allowed to stand for an additional 10minutes at room temperature to allow color development. The inhibitionof arginase is computed by measuring the optical density (OD) of thereaction mixture at 530 nm and normalizing the OD value to percentinhibition observed in the control. The normalized OD is then used togenerate a dose-response curve by plotting the normalized OD valuesagainst log [concentration] and using regression analysis to compute theIC₅₀ values.

Arginase IC₅₀ Values

TABLE 1 Example rhArg I rhArg II No IUPAC Name (IC₅₀) (IC₅₀) 248(5-amino-5-(1-(4-chlorobenzyl)-1H- >100 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 249 (5-amino-5-(1-(2-fluoro-5-nitrophenyl)- >1001H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 2502-(5-(1-amino-5-boronopentyl)-1H- >100 tetrazol-1-yl)acetic acidhydrochloride. 251 (5-amino-5-(1H-tetrazol-5- >100 yl)hexyl)boronic acidhydrochloride. 252 (6-amino-6-(1H-tetrazol-5- >100 yl)hexyl)boronic acidhydrochloride. 253 (5-amino-5-(1-(2-((2-fluorobenzyl)amino)- 9.4 82-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride 254(5-amino-5-(1-benzyl-1H-tetrazol-5- 180 yl)pentyl)boronic acidhydrochloride. 255 (5-(methylamino)-5-(1H-tetrazol-5- >500yl)pentyl)boronic acid hydrochloride. 256(5-amino-5-(1-(3-fluorobenzyl)-1H- >100 tetrazol-5-yl)pentyl) boronicacid hydrochloride. 257 (5-amino-5-(1-phenethyl-1H-tetrazol-5- >100yl)petyl)boronic acid hydrochloride 258(5-amino-5-(1-cyclohexyl-1H-tetrazol-5- >100 yl)pentyl)boronic acidhydrochloride. 259 (5-amino-5-(1H-tetrazol-5- >500 yl)pentyl)boronicacid hydrochloride. 260 (5-amino-5-(1-(2-(benzylamino)-2- 40oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride 261(5-(1-(2-fluoro-5-nitrophenyl)-1H-tetrazol- >5005-yl)-5-morpholinopentyl)boronicacid hydrochloride. 262(5-amino-5-(1-(2-morpholino-5- >500 nitrophenyl)-1H-tetrazol-5-yl)pentyl)boronicacid hydrochloride. 262 5-amino-5-(1H-tetrazol-5- >100yl)hexyl)boronicacid hydrochloride. 263(5-amino-5-(1-(2-((4-chlorobenzyl) 14 7amino)-2-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride264 (5-amino-5-(1-(2-oxo-2-(((S)-1- 13phenylethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 265 (5-amino-5-(1-(2-oxo-2-((thiophen-2- 23ylmethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 266 (5-Amino-5-(1-(2-oxo-2- 15 13(phenethylamino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 267 (5-amino-5-(1-(2-((1-benzylpiperidin-4- 248yl)amino)-2-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 268 (5-amino-5-(1-(2-(cyclopropylamino)-2- 21oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 269(5-amino-5-(1-(2-((2- >500 morpholinoethyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 270(5-amino-5-(1-(2-((3,4- 29 dimethoxyphenethyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 271(5-amino-5-(1-(2-(butylamino)-2- 14oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 272(5-amino-5-(1-(2-oxo-2-(prop-2-yn-1- 17 12 ylamino)ethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 273(5-amino-5-(1-(2-(4-benzylpiperazin-1-yl)- >5002-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride. 274(5-amino-5-(1-(2-morpholino-2-oxoethyl)- 3401H-tetrazol-5-yl)pentyl)boronic acid hydrochloride 275(5-amino-5-(1-(2-oxo-2-(pyrrolidin-1- 448yl)ethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 276(5-amino-5-(1-(2-((3- 50 chlorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 277(5-amino-5-(1-(2-((2- 55 chlorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 278(5-amino-5-(1-(2-oxo-2-((pyridin-3- 58ylmethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 279 (5-amino-5-(1-(2-((4- 45methoxybenzyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. 280 (5-amino-5-(1-(2-oxo-2-((pyridin-4- 65ylmethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 281 (5-amino-5-(1-(3-((4- 70chlorobenzyl)amino)-3-oxopropyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride 282 (5-amino-5-(1-(3-oxo-3- 110(phenethylamino)propyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 283 4-(5-(1-amino-5-boronopentyl)-1H- 250tetrazol-1-yl)butanoic acid hydrochloride 284(5-(1-(2-(1H-indol-3-yl)ethyl)-1H-tetrazol- 1155-yl)-5-aminopentyl)boronic acid hydrochloride. 285(5-amino-5-(1-(2-(benzyl(2- 155 hydroxyethyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 286(5-amino-5-(1-(2-(benzyl(methyl)amino)- 80 2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 287 (5-amino-5-(1-(2-(((S)-1-(4-35 chlorophenyl)ethyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 288(5-amino-5-(1-(1-phenylethyl)-1H- 210 tetrazol-5-yl)pentyl)boronic acidhydrochloride. 289 (5-amino-5-(1-((S)-1-phenylethyl)-1H- 155tetrazol-5-yl)pentyl)boronic acid hydrochloride. 290(5-amino-5-(1-((R)-1-phenylethyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 291 (5-amino-5-(1-((S)-1-(4- <101chlorophenyl)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride.292 (5-amino-5-(1-((R)-1-(4- <101 chlorophenyl)ethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 293 (5-amino-5-(1-((R)-1-(4- <101methoxyphenyl)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 294 (5-amino-5-(1-(4-fluorobenzyl)-1H- <101tetrazol-5-yl)pentyl)boronic acid hydrochloride. 295(5-amino-5-(1-(2-fluorobenzyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 296 (5-amino-5-(1-(3-chlorobenzyl)-1H- <101tetrazol-5-yl)pentyl)boronic acid hydrochloride. 297(5-amino-5-(1-(2-chlorobenzyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 298 (5-amino-5-(1-(4-bromobenzyl)-1H- <101tetrazol-5-yl)pentyl)boronic acid hydrochloride. 299(5-amino-5-(1-(4-cyanobenzyl)-1H- <101 tetrazol-5-yl)pentyl)boronic acidhydrochloride. 300 (5-amino-5-(1-(2,4-dichlorobenzyl)-1H- <101tetrazol-5-yl)pentyl)boronic acid hydrochloride. 301(5-amino-5-(1-(3,4-dichlorobenzyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 302 (5-amino-5-(1-(4-bromo-2-fluorobenzyl)- <1011H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 303(5-amino-5-(1-(2-methoxybenzyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 304 (5-amino-5-(1-(3-hydroxy-1- <101phenylpropyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride. 305(5-amino-5-(1-(pyridin-3-ylmethyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 306 (5-amino-5-(1-(thiophen-2-ylmethyl)-1H- <101tetrazol-5-yl)pentyl)boronic acid hydrochloride. 307(5-amino-5-(1-(4-fluorophenethyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 308 (5-amino-5-(1-(3,4-dimethoxyphenethyl)- <1011H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 309(5-amino-5-(1-(2-methoxyphenethyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 310 (5-amino-5-(1-(4-hydroxyphenethyl)-1H- <101tetrazol-5-yl)pentyl)boronic acid hydrochloride. 311(5-amino-5-(1-(3-methoxyphenethyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 312 (5-amino-5-(1-(3-phenylpropyl)-1H- <101tetrazol-5-yl)pentyl)boronic acid hydrochloride. 313(5-amino-5-(1-(4-bromophenethyl)-1H- <101 tetrazol-5-yl)pentyl)boronicacid hydrochloride. 314 (5-amino-5-(1-(2,5-difluorobenzyl)-1H- <101tetrazol-5-yl)pentyl)boronic acid hydrochloride. 315(5-amino-5-(1-(2-((2,4- 9.1 difluorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 316(5-amino-5-(1-(2-((4- 33 methylbenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 317(5-amino-5-(1-(2-((4- 75 chlorophenethyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 318(5-amino-5-(1-(2-((4-chloro-2- 15.5 18.6fluorobenzyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. 319 (5-amino-5-(1-(2-((2,6- 12.4difluorobenzyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. 320 (5-amino-5-(1-(2-((4-cyanobenzyl)amino)- 432-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride. 321(5-amino-5-(1-(1-((4- 150 chlorobenzyl)amino)-3-methyl-1-oxobutan-2-yl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride. 322(5-amino-5-(1-(1-((4- 110 chlorobenzyl)amino)-4-methyl-1-oxopentan-2-yl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride 323(5-amino-5-(1-(2-((4- 55 bromobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 324(6-amino-6-(1-(2-(benzylamino)-2- 120oxoethyl)-1H-tetrazol-5-yl)hexyl)boronic acid hydrochloride. 325(6-amino-6-(1-(2-((4- 7.8 chlorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)hexyl)boronic acid hydrochloride 326(6-amino-6-(1-(2-((2,4- 13 dichlorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)hexyl)boronic acid hydrochloride. 327(6-amino-6-(1-(2-oxo-2-(prop-2-yn-1- 38 ylamino)ethyl)-1H-tetrazol-5-yl)hexyl)boronic acid hydrochloride. 328 (6-amino-6-(1-(2-oxo-2- <110(phenethylamino)ethyl)-1H-tetrazol-5- yl)hexyl)boronic acidhydrochloride. 329 (5-amino-5-(1-(2-oxo-2- 16.8(((perfluorophenyl)methyl)amino)ethyl)- 1H-tetrazol-5-yl)pentyl)boronicacid hydrochloride. 330 (5-amino-5-(1-(2-oxo-2-((2,3,4,5- 13tetrafluorobenzyl)amino)ethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. 331 (5-amino-5-(1-(2-oxo-2-((2,4,6- 12.5trifluorobenzyl)amino)ethyl)-1H-tetrazol- 5-yl)pentyl)boronic acidhydrochloride. 332 (5-amino-5-(1-(2-(((6-chloropyridin-3- 5.5yl)methyl)amino)-2-oxoethyl)-1H-tetrazol- 5-yl)pentyl)boronic acidhydrochloride. 333 (5-amino-5-(1-(2-((3-fluorobenzyl)amino)- 10.62-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride. 334(5-amino-5-(1-(2-((2,3- 11.5 56 difluorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 335(5-amino-5-(1-(2-((2,5- 13 difluorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid. hydrochloride. 336(5-amino-5-(1-(2-((3,5- 19 difluorobenzyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 337(5-amino-5-(1-(2-oxo-2-((2,3,4- 49trifluorobenzyl)amino)ethyl)-1H-tetrazol- 5-yl)pentyl)boronic acidhydrochloride. 338 (5-amino-5-(1-(2-oxo-2-((2,3,5- 43trifluorobenzyl)amino)ethyl)-1H-tetrazol- 5-yl)pentyl)boronic acidhydrochloride. 339 (5-amino-5-(1-(2-oxo-2-((3,4,5- 56trifluorobenzyl)amino)ethyl)-1H-tetrazol- 5-yl)pentyl)boronic acidhydrochloride. 340 (5-amin o-5-(1-(2-oxo-2-((2,3,6-trifluorobenzyl)amino)ethyl)-1H-tetrazol- 5-yl)pentyl)boronic acidhydrochloride. 341 (5-amino-5-(1-(2-oxo-2-((2,3,5,6- 33tetrafluorobenzyl)amino)ethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. 342 (5-amino-5-(1-(2-((3,4- 51difluorobenzyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. 343 (5-amino-5-(1-(2-oxo-2-((2,4,5- 15trifluorobenzyl)amino)ethyl)-1H-tetrazol- 5-yl)pentyl)boronic acidhydrochloride. 344 (5-amino-5-(1-((1-(4- 24chlorobenzyl)piperidin-4-yl)methyl)-1H- tetrazol-5-yl)pentyl)boronicacid hydrochloride. 345 (5-amino-5-(1-(2-oxo-2-(((R)-1- 15phenylethyl)amino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 346 (5-amino-5-(1-(2-(((1-(2-fluoroethyl)-1H- 231,2,3-triazol-4-yl)methyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 347(5-amino-5-(1-(2-(4- 95 chlorobenzamido)ethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride 348(5-amino-5-(1-(2-(((1-(4-chlorobenzyl)- 271H-1,2,3-triazol-4-yl)methyl)amino)-2-oxoethyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride 349(5-(1-(2-((4-chlorobenzyl)amino)-2- 120oxoethyl)-1H-tetrazol-5-yl)-5-((pyridin-4- ylmethyl)amino)pentyl)boronicacid hydrochloride. 350 (5-(4-(aminomethyl)piperidin-1-yl)-5-(1- 150(2-((4-chlorobenzyl)amino)-2-oxoethyl)- 1H-tetrazol-5-yl)pentyl)boronicacid hydrochloride. 351 (5-(1-(2-((4-chlorobenzyl)amino)-2- 250oxoethyl)-1H-tetrazol-5-yl)-5-((1- methylpiperidin-4-yl)amino)pentyl)boronic acid hydrochloride. 352(5-(1-(2-(([1,1′-biphenyl]-4- 250ylmethyl)amino)-2-oxoethyl)-1H-tetrazol- 5-yl)-5-aminopentyl)boronicacid. 353 (5-(1-(2-(((6-(1H-imidazol-1-yl)pyridin-3- 130yl)methyl)amino)-2-oxoethyl)-1H-tetrazol- 5-yl)-5-aminopentyl)boronicacid hydrochloride. 354 (5-amino-5-(1-(2-((4- 255chlorophenyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. 355 (+)-(R)-(5-amino-5-(1-(2-oxo-2-(prop-2- 15 30yn-1-ylamino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride.356 (−)-(S)-(5-amino-5-(1-(2-oxo-2-(prop-2- 28 35yn-1-ylamino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride.357 (+)-(R)-(5-amino-5-(1-(2-((4- 55 137chlorobenzyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. 358 (−)-(S)-(5-amino-5-(1-(2-((4- 12 6chlorobenzyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. (SHK227) 359 (+)-(R)-(5-amino-5-(1-(2-((2- 3.4 2.9fluorobenzyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. (SHK242) 360 (−)-(S)-(5-amino-5-(1-(2-((2- 36.4 5fluorobenzyl)amino)-2-oxoethyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride. 361 (+)-(R)-(5-amino-5-(1-(2-oxo-2- 10.5 4.0(phenethylamino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. (SHK277) 362 (−)-(S)-(5-amino-5-(1-(2-oxo-2- 13.2 10.2(phenethylamino)ethyl)-1H-tetrazol-5- yl)pentyl)boronic acidhydrochloride. 363 (5-amino-5-(1-(2-((4-fluorobenzyl)amino)- 342-oxoethyl)-1H-tetrazol-5- yl)pentyl)boronic acid hydrochloride. 364(5-amino-5-(1-(5-amino-2-fluorophenyl)- 2501H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 3655-amino-5-(1-(5-amino-2- 300 morpholinophenyl)-1H-tetrazol-5-yl)pentyl)boronic acid hydrochloride. 366 (5-amino-5-(1-(5-amino-2-(1,1-200 dioxidothiomorpholino)phenyl)-1H- tetrazol-5-yl)pentyl)boronic acidhydrochloride.

Further data for some compounds of the present invention is disclosed inVan den Berg M. P. M. et al. “Pharmacological screening identifiesSHK242 and SHK277 as novel arginase inhibitors with efficacy againstallergen-induced airway narrowing in vitro and in vivo” Journal ofPharmacology and Experimental Therapeutics Apr. 13, 2020,jpet.119.264341; DOI: 10.1124/jpet.119.264341.

1. A compound of formula (I):

wherein n is 1 or 2; R¹ is hydrogen or an alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group,all of which groups may optionally be substituted; R² is hydrogen or analkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl group, all of which groups may optionally be substituted,and R³ is hydrogen; or R² and R³ together are part of an optionallysubstituted heterocycloalkyl or heteroaryl group; and R⁴ is hydrogen ormethyl. or a pharmaceutically acceptable salt, solvate or hydrate or apharmaceutically acceptable formulation thereof.
 2. The compoundaccording to claim 1, wherein R⁴ is hydrogen.
 3. The compound accordingto claim 1, wherein R² and R³ are hydrogen.
 4. The compound according toclaim 1, wherein R¹ is a group of formula —CH₂—C(═O)—NH—R⁵, a group offormula —CH₂—CH₂—C(═O)—NH—R⁵, or a group of formula—CH₂—C(═O)—N(CH₃)—R⁵, wherein R⁵ is an alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group,all of which groups may optionally be substituted.
 5. The compoundaccording to claim 1, wherein R¹ is a group of formula -L¹-Cy¹-L²-Cy²,wherein L¹ and L² are independently selected from a bond, a C₁₋₄ alkylgroup or a C₁₋₄ heteroalkyl group; Cy¹ is a C₃₋₇ cycloalkylene group, aheterocycloalkylene group containing from 3 to 7 ring atoms selectedfrom O, S, N and C, a phenylene group or a heteroarylene groupcontaining 5 or 6 ring atoms selected from O, S, N and C, all of whichgroups may optionally be substituted; and Cy² is a C₃₋₇ cycloalkylgroup, a heterocycloalkyl group containing from 3 to 7 ring atomsselected from O, S, N and C, a phenyl group or a heteroaryl groupcontaining 5 or 6 ring atoms selected from O, S, N and C, all of whichgroups may optionally be substituted.
 6. The compound according to claim1, having the following formula (II):

wherein R⁵ is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted; or a pharmaceutically acceptable salt,solvate or hydrate or a pharmaceutically acceptable formulation thereof.7. The compound according to claim 1, having the following formula(III):

wherein R⁵ is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl group, all of which groups mayoptionally be substituted; or a pharmaceutically acceptable salt,solvate or hydrate or a pharmaceutically acceptable formulation thereof.8. The compound according to claim 4, wherein R⁵ is a group of formula—CH₂—R⁶, —CH₂CH₂—R⁶ or —CH(CH₃)—R⁶ wherein R⁶ is an alkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group,all of which groups may optionally be substituted.
 9. The compoundaccording to claim 8, wherein R⁶ is a C₁₋₄ alkyl, a C₂₋₄ alkenyl, a C₂₋₄alkynyl or a C₁₋₄ heteroalkyl group.
 10. The compound according to claim8, wherein R⁶ is selected from the following groups, all of which mayoptionally be substituted: C₃₋₇ cycloalkyl, phenyl, heterocycloalkylcontaining from 3 to 7 ring atoms selected from C, N, O and S andheteroaryl containing 5 or 6 ring atoms selected from C, N, O and S. 11.A pharmaceutical composition comprising a compound according to claim 1or a pharmaceutically acceptable salt, solvate or hydrate thereof,optionally in combination with a pharmaceutically acceptable carrierand/or adjuvant.
 12. A method of treating a disease that is associatedwith arginase activity, comprising administering a compound of claim 1.13. The compound according to claim 6, wherein R⁵ is a group of formula—CH₂—R⁶, —CH₂CH₂—R⁶ or —CH(CH₃)—R⁶ wherein R⁶ is an alkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group,all of which groups may optionally be substituted.
 14. The compoundaccording to claim 13, wherein R⁶ is a C₁₋₄ alkyl, a C₂₋₄ alkenyl, aC₂₋₄ alkynyl or a C₁₋₄ heteroalkyl group.
 15. The compound according toclaim 13, wherein R⁶ is selected from the following groups, all of whichmay optionally be substituted: C₃₋₇ cycloalkyl, phenyl, heterocycloalkylcontaining from 3 to 7 ring atoms selected from C, N, O and S andheteroaryl containing 5 or 6 ring atoms selected from C, N, O and S. 16.The compound according to claim 7, wherein R⁵ is a group of formula—CH₂—-R⁶, —CH₂CH₂—R⁶ or —CH(CH₃)-R⁶ wherein R⁶ is an alkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group,all of which groups may optionally be substituted.
 17. The compoundaccording to claim 16, wherein R⁶ is a C₁₋₄ alkyl, a C₂₋₄ alkenyl, aC₂₋₄ alkynyl or a C₁₋₄ heteroalkyl group.
 18. The compound according toclaim 16, wherein R⁶ is selected from the following groups, all of whichmay optionally be substituted: C₃₋₇ cycloalkyl, phenyl, heterocycloalkylcontaining from 3 to 7 ring atoms selected from C, N, O and S andheteroaryl containing 5 or 6 ring atoms selected from C, N, O and S. 19.The method of claim 12, wherein the disease is asthma, COPD and allergicrhinitis.